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QuinolineasaPrivilegedScaffoldinCancerDrugDiscovery

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Quinoline as a Privileged Scaffold in Cancer Drug Discovery

V.R. Solomon1,2 and H. Lee*,1,2,3

1Tumour Biology Group, Northeastern Ontario Regional Cancer Program at the Sudbury Regional Hospital, 41 Ramsey Lake Road,

Sudbury, Ontario P3E 5J1, Canada

2Department of Biology, Laurentian University, 935 Ramsey Lake Road, Sudbury, Ontario P3E 2C6, Canada

3Medical Sciences Division, the Northern Ontario School of Medicine, 935 Ramsey Lake Road, Sudbury, Ontario P3E 2C6, Canada

Abstract: Quinoline (1-azanaphthalene) is a heterocyclic aromatic nitrogen compound characterized by a double-ring structure that con-tains a benzene ring fused to pyridine at two adjacent carbon atoms. Quinoline compounds are widely used as “parental” compounds to synthesize molecules with medical benefits, especially with anti-malarial and anti-microbial activities. Certain quinoline-based com-pounds also show effective anticancer activity. This broad spectrum of biological and biochemical activities has been further facilitated by the synthetic versatility of quinoline, which allows the generation of a large number of structurally diverse derivatives. This includes numerous analogues derived from substitution of the quinoline ring system, and derivatization of quinoline ring structure. Quinoline and its analogs have recently been examined for their modes of function in the inhibition of tyrosine kinases, proteasome, tubulin polymeriza-tion and DNA repair. In this review, we have summarized our knowledge on quinoline compounds with respect to their anticancer activi-ties, mechanisms of action, structure-activity relationship (SAR), and selective and specific activity against various cancer drug targets. In particular, we focus our review on in vitro and in vivo anticancer activities of quinoline and its analogs in the context of cancer drug development and refinement.

Keywords: Quinoline, cancer, drug discovery, anticancer activity, chemotherapy.

INTRODUCTION

Quinoline (1-azanaphthalene) is a heterocyclic aromatic nitro-gen compound characterized by a double-ring structure that con-tains a benzene ring fused to pyridine at two adjacent carbon atoms (Fig. 1) [1]. Quinoline derivatives have been the intense research interest for many years since the quinoline structure is found in a large number of natural products as well as in numerous commer-cial products such as pharmaceuticals, fragrances, and dyes. In particular, quinoline alkaloids are found in many different plants including Berberidaceae, Fumariaceae, Papavaraceae and Rutaceae [2-6]. A number of these compounds are planar aromatic heterocy-cles that have shown cytotoxic activity by inhibiting topoisomerase II [6].

N

1

2

3

45

6

7

8

Fig. (1). Chemical structure and numbering of quinoline.

Quinoline compounds are widely used as “parental” compounds to synthesize molecules with medical benefits, especially with anti-malarial and anti-microbial activities [7, 8]. The quinoline ring system containing drugs such as quinine, chloroquine, mefloquine, and amodiaquine are used as efficient drugs for the treatment of malaria [9]. In addition, certain quinoline-based compounds show effective anticancer activity (reviewed in [10]). This broad spec-trum of biological and biochemical activities has been further facili-tated by the synthetic versatility of quinoline, which allows creating a large number of structurally diverse derivatives.

Recent studies have shown that quinoline and its analogs can inhibit tyrosine kinases, proteasome, tubulin polymerization and DNA repair. In this review, we summarize our knowledge on qui-noline and its analogs with respect to their biological activities, mechanisms of action, structure-activity relationship (SAR), and

*Address correspondence to this author at the Tumour Biology Group, Northeastern Ontario Regional Cancer Program at the Sudbury Regional Hospital, 41 Ramsey Lake Road, Sudbury, Ontario, P3E 5J1, Canada; Tel: +1 705 522-6237, ext. 2703; Fax: +1 705 523 7326; E-mail: hlee@hrsrh.on.ca

selective and specific activity against various cancer drug targets. We will also focus our review on in vitro and in vivo anticancer activities of quinoline ring-based analogs in the context of cancer drug development and refinement.

QUINOLINE-BASED COMPOUNDS AS PI3K-PKB INHIBI-

TORS

The PI3K-PKB pathway is one of the major signaling pathways highly active in cancer, often due to deletions, activating mutations, and/or amplification of its players [11]. The node of the pathway is PKB (also known as Akt), a serine/threonine protein kinase respon-sible for the phosphorylation of downstream effectors involved in many important cellular processes such as metabolism, growth, proliferation, survival, and angiogenesis [12, 13]. Activation of PKB/Akt requires the following three sequential events: (i) recruit-ment of substrates to the plasma membrane by phosphatidylinosi-tol-3,4,5-trisphosphate (PIP3), the product of the PI3K lipid kinase. This step is negatively regulated by the tumor suppressor phospha-tase and tensin homolog deleted on chromosome 10 (PTEN). The second step is phosphorylation of the recruited PKB/Akt at the Thr-308 (PKB numbering) residue by the 3-phosphoinositide-dependent protein kinase-1 (PDK1). Finally, PKB/Akt is addition-ally phosphorylated at Ser-473 (PKB numbering) by PDK2. The identity of PDK2 is not completely clear as several potential candi-dates have been suggested, including mTORC2 (a complex formed by mTor and rector) and ILK (integrin-linked kinase) [11-13].

Given the role of the PI3K-PKB/Akt pathway in the biology of human cancers, some of the components of this signaling cascade have recently become the focal point of drug discovery research. Augur et al. developed the quinoline-based PI3K inhibitor com-pound 1 (Fig. 2) by structure-based drug design, which entered a dose-escalation study in patients with refractory malignancies [14]. X-ray crystallography showed that the thiazolidinedione (TZD) ring of compound 1 interacts with the catalytic lysine (Lys-833) within the ATP-binding pocket of PI3K . The authors found that the ATP-binding pocket of PI3K could potentially accommodate a larger group. Therefore, the authors hypothesized that completely filling the empty space of the enzyme pocket could lead to developing inhibitors with improved potency and selectivity. Based on this hypothesis, the authors synthesized a series of quinoline com-pounds, which led to the identification of compound 2 (Fig. 2), an extraordinarily potent inhibitor of PI3K (p110 /p85 ) at a pico-

2 Current Medicinal Chemistry, 2011 Vol. 18, No. 1 Solomon and Lee

molar concentration (PI3K IC50, 0.04 nM) [15]. Biochemical as-says showed that compound 2 was indeed much more potent than compound 1 (PI3K IC50, 2 nM), and was the most potent PI3K inhibitor reported so far. Cell-based assays showed that compound 2 caused a significant reduction of Akt phosphorylation at the Ser-473 residue. As expected, the treatment of cells with compound 2 at a nanomolar range resulted in deactivation of PI3K downstream proteins, including PKB/Akt, mTOR, and p70S6K. Compound 2 also arrested cell cycle progression at G1 phase, and inhibited cell proliferation in a large panel of cell lines examined, including T47D and BT474 breast cancer lines [15].

QUINOLINE-BASED COMPOUNDS AS INHIBITORS OF

EPIDERMAL GROWTH FACTOR RECEPTORS

Receptor tyrosine kinases play crucial roles in the regulation of signal transduction pathways that are involved in cell differentiation and proliferation [16]. Several receptor tyrosine kinases are known to be activated in cancer cells, which may drive tumor growth and progression. For example, a strong correlation has been found be-tween poor prognosis of solid tumors with high levels of epidermal growth factor receptor (EGFR/Her-1/ErbB-1), a 170 kDa glycopro-tein that contains an extracellular ligand-binding domain, a trans-membrane region, and an intracellular domain with kinase activity [17, 18]. Thus, EGFR can be an attractive target for anticancer compounds that bind specifically to the receptor and inhibit its tyro-sine kinase (TK)-mediated signal transduction pathway in cancer cells [19, 20]. This class of promising small molecules includes 4-anilinoquinazolines, anilinoquinolines, and pyrrolopyrimidines (Fig. 3) [19, 20]. Various approaches have been taken to further improve the potency and selectivity, which led to the discovery of EKB-569 (Fig. 3) [21]. As this compound is a potent, selective, and irreversible inhibitor of EGFR, it is currently being devel-oped as an effective anticancer agent [21].

Wissner et al. performed molecular docking experiments on 4-anilinoquinazoline analogs to examine the interactions between the quinazoline core and EGFR [22]. The authors hypothesized that the C-3 nitrogen of quinazoline may interact with EGFR via a bridging water molecule. The authors further hypothesized that replacement of this atom on the quinazoline ring of PD153035 with a carbon atom containing an electron-withdrawing carbonitrile (CN) group might retain the charge distribution that would result from such an interaction with EGFR. The interactions are thought to occur by forming covalent bonds between compounds and Cys residues (Cys-773 in EGFR and Cys-805 in HER-2) within the ATP binding pocket of the enzymes. Based on this hypothesis, Wissner et al. synthesized a series of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles (EKB-569) to inhibit effectively the EGFR and HER-2 activity [23, 24]. EKB-569 carries a Michael acceptor at the 6-position, which forms a covalent bond with Cys-773 located within the ATP binding pocket of EGFR. The water-solubilizing dimethy-lamino group at the end of the Michael acceptor serves as an in-tramolecular base catalyst operating via a cyclic five-membered ring mechanism to catalyze the Michael addition process [23, 24]. As a result, EKB-569 showed a potent antitumor activity in EGFR-

dependent tumor models. However, EKB-569 was not very effi-cient in HER-2 dependent tumor models. Therefore, researchers tried to develop compounds that can irreversibly inhibit HER-2.

Tsou et al. synthesized a series of 6,7-disubstituted 4-(arylamino)quinoline-3-carbonitriles modified with a variety of lipophilic substitutes on the arylamino ring [25]. A SAR-based study suggested that attaching a large lipophilic group at the para position of the 4-(arylamino) ring showed improved potency in inhibiting HER-2 kinase. This modification improved water solubil-ity and, thus, significantly enhanced biological activities. Among this series of compounds, HKI-272 was found to bind irreversibly to HER-2 in the BT474 cell model [25]. In vitro studies showed that HKI-272 was highly active against HER-2-overexpressing human breast cancer cell lines. HKI-272 reduced HER-2 receptor auto-phosphorylation in cells at doses consistent with the inhibition of cell proliferation, and functions as an irreversible binding inhibitor, most likely by targeting a cysteine residue in the ATP-binding pocket of the receptor [11]. In agreement with the predicted effect of HER-2 inactivation, HKI-272 treatment results in the inhibition of downstream signal transduction events and cell cycle arrest at G1/S. HKI-272 also inhibits EGFR kinase and, thus, the prolifera-tion of EGFR-dependent cells. In vivo studies showed that HKI-

272 is active in both HER-2 and EGFR-dependent tumor xenograft models [26, 27].

Abouzid et al. synthesized two series of new 6-alkoxy-4-substituted-aminoquinazolines (3) and their bioisoteric quinoline congeners (4) by a hybrid approach (Fig. 3) [13]. In this series of quinoline derivatives, compounds 4 and 5 were most potent with IC50 at 1.67 and 2.84 nM, respectively [13]. A SAR-based study concluded that the quinazoline derivatives with the five-membered heterocyclic sulfonamido moiety at the C-4 of the anilino group are more active than their quinoline analogues [28]. Apart from these studies, Lu et al. synthesized 3-nitroquinoline series of compounds (6, Fig. 3), and evaluated their antiproliferative effects on the A431 human epidermoid carcinoma and MDA-MB-468 breast cancer cell lines [29]. Analysis of these compounds by SAR suggested that both the aniline portion and the 6,7-dialkoxy substituent may play important roles in determining the potency of the 3-nitroquinoline series as kinase inhibitors. It is noteworthy that the substitution within the aniline moiety does not necessarily be an electro-withdrawing group at the meta position. Pawar et al. synthesized a series of 4-anilinoquinolines and examined its antiproliferative effects on clinically relevant mutant variants of EGFR cell lines [30]. The authors found that compounds 7 and 8 (Fig. 3) were highly effective kinase inhibitors [30].

QUINOLINE-BASED COMPOUNDS AS MITOGEN-

ACTIVATED PROTEIN KINASE INHIBITORS

The mitogen-activated protein kinase (MAPK) pathway is a major pathway in the kinase signaling cascade from growth factors to the cell nucleus (i.e., gene expression). The MAPK pathway involves a heirarchy of kinases at multiple levels: MAP kinases (or ERKs, for extracellular signal-regulated kinases) and MAP kinase

N

NN

NH

O

O2S

F FN

N

HN S

O

O

(1) (2)

Fig. (2). Quinoline-based PI3K inhibitors.

Quinoline Based Anticancer Agents Current Medicinal Chemistry, 2011 Vol. 18, No. 1 3

kinases (or MEKs, for MAPK/ERK kinases) [31-33]. MEK is acti-vated by phosphorylation at Ser-218 and -222 residues by upstream kinases such as the Raf kinase family which in, turn, phosphory-lates MAPK [34, 35]. The activated MAPK proteins translocate to the nucleus where they activate downstream targets, resulting in the activation of cell growth and proliferation. Therefore, blocking the MAPK pathway provides a unique opportunity of inhibiting uncon-trolled cell growth and, thus, rendering therapeutic effects on cancer [35, 36].

By a high-throughput screening approach, Wissner et al. identi-fied the lead compound of 4-anilino-3-cyanoquinolines as inhibitors of MAP kinase kinase [37]. In continuation of this study, Zhang et al. developed a series of 3-cyano-4-(phenoxyanilino)cyanoquino-lines as MEK inhibitors [38]. The authors found that compound 9 (Fig. 4) with a methoxy group at the C-6 position and a morpholi-noalkoxy group at the C-7 maintained potent activity. The authors examined compound 9 for its ability to inhibit cell growth in Colo205, Lovo, and SW620 human colon tumor lines [38]. Further,

they also carried out a SAR experiment with a series of 4-anilino-3-cyano-6,7-dialkoxyquinolines with different substitutions on the 4-anilino group. They found that the replacement of the oxygen with an amino group greatly decreased activity, while replacement of the same oxygen with a methylene group retained the activity [39]. This data suggests that a hydrogen bond donor is detrimental to maintaining its activity. A flexible linkage between the two phenyl rings is crucial as the activity decreased by more than two orders of magnitude when a phenyl group was attached directly to the aniline at the para-position. The size of the phenoxy group is also impor-tant for activity, as replacing it with a methoxy, a hydroxy, or a methylsulfanyl group invariably led to a decrease in activity. The activity was reduced by 6- to 7-fold when a 4-chloro was intro-duced to the phenoxy group. The position of the phenoxy group on the aniline was also very important, since the activity was greatly reduced when it was moved from the para-position to the meta-position. Moving the phenoxy to the ortho-position further reduced activity [39]. The best activity was obtained when a phenyl or a thienyl group was attached to the para-position of the aniline

N

N

O

ON

HN

F

ClO

N

N

O

O

HN Br

NO

O

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CN

NO

HN

HN Cl

CN

F

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OR1

R2

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R3

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Cl

R1 R2

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R1 R2

CH3

(3)

GefitinibPD153035 EKB1

EKB-569

4 R1, R2 = Cl, R3 = H

5 R1, R2 = H, R3 = OH (6)

NO

HN

HN Cl

CN

O

N

O

N

HKI-272

N

HN BrHN

N

ON

N

HN BrHN

N

O

(7) (8) Fig. (3). Quinoline-based chemical structure of EGFR-TK inhibitors.

4 Current Medicinal Chemistry, 2011 Vol. 18, No. 1 Solomon and Lee

through a hydrophobic linker such as an oxygen, sulfur, or methyl-ene group. The most active compound 10 (Fig. 4) showed low nanomolar IC50 value against MEK (IC50, 10 nM), and potent in-hibitory effect on the LoVo cell growth (human colon tumor line, IC50, 7 nM) [39].

In order to improve the aqueous solubility of active compound 10, Berger et al. carried out SAR-based analysis, in which authors introduced water-solubilizing groups at the C-7 position [40]. Of these newly synthesized compounds, 11 was identified as a potent MEK1 inhibitor (IC50, 3 nM), which was highly active (IC50, 7 nM) against LoVo cells, a human colon tumor line with a K-Ras muta-tion [40]. Western blot analysis revealed that this compound strongly inhibited phosphorylation of ERK, although it also inhib-ited phosphorylation of MEK, an unintended off-target [41]. Com-pound 11 displayed potent activity both in vitro and in vivo i.p. However, its solubility in aqueous media was poor and, thus, undetectable in the plasma following oral application in vivo [40, 41]. To improve oral bioavailablity, Berger et al. modified the C-7 position with an alkenyl substitute [42]. The C-7 substituted allylic amine analogs appeared to be slightly less potent than the similarly substituted homoallylic amines. However, compound 12 was chosen to study further, as it showed a good potency profile by an in vitro study. The selectivity of 12 was ascertained against a panel of 17 kinases, where activity was observed against EGFR, Src, Lyn, and IR kinases. Western blot analysis with WM-266 cells demonstrated that compound 12 inhibited phosphorylation of ERK, while additional kinase pathways examined showed no inhibition at up to 10 M concentration [42].

Cernuchova et al. reported a new series of 4-amino-3-acetylquinoline (13, Fig. 4) with substantial cytotoxic effects on murine L1210 leukemia cells [43]. The mode of cell death by this compound was mainly due to apoptosis caused by reactive oxygen species (ROS)-mediated mitochondrial dysfunction [44].

QUINOLINE-BASED COMPOUNDS AS ALK5 INHIBITORS

The antitumor effects of TGF- in tumor growth and metastases have been documented in a number of animal models, although this multifunctional cytokine shows complex and, sometimes, paradoxi-cal effects on the development of neoplasia and tumor progression

[45-47]. The type I TGF- receptor (ALK5), an intracellular ser-ine/threonine kinase required for TGF- signaling is a particularly attractive cancer therapeutic target. Small molecules blocking the ATP-binding site of ALK5 can be effective anticancer therapeutics [45-47]. To identify ALK5 inhibitors, Singh et al. screened 200,000 commercially available compounds in an in silico database [48]. The query returned 87 compounds that fit the pharmacophore model requirements. Among the 87 compounds, 14 (Fig. 5) was the most effective ALK5 inhibitor (IC50, 27 nM) [48]. Compound 14 (4-[3-pyridin-2-yl-1H-pyrazol-4-yl]-quinoline) satisfied the query's overall shape and volume requirements, and contained three re-quired aryl groups as well as moieties that can satisfy the hydrogen bonding requirements. The authors showed that this compound could indeed inhibit the autophosphorylation of ALK5 in a cell-free ALK5 kinase domain assay. Importantly, compound 14 also showed dose-dependent inhibition of the TGF- -stimulated PAI-luciferase reporter in HepG2 cells (IC50, 60 nM) [48]. In addition, compound 14 at 10 M showed high selectivity when assayed against a panel of 35 mammalian kinases, and showed the highest activity against p38 (90% inhibition at 10 M). However, it was only moderately active against Lck, Raf and Fyn (50-70% inhibi-tion at 10 M) [48].

Based on this information, Sawyer et al. carried out a SAR-based study on compound 14, in which authors introduced modifi-cations on the pyridinyl ring system at the C-7 position of the qui-noline ring [49]. The authors found that the overall activity in-creased when a 6-methyl or 6-ethyl group was added to the pyridinyl ring system. However, larger branched isopropyl groups at this position led to a decrease in biological activity. The best overall activity was observed with compounds with electron-donors at the C-7 position of the quinolin-4-yl moiety. In contrast, oxida-tion of thioether to the corresponding sulfone at the C-7 position led to a significant loss of activity. Enzymatic and T R-1-dependent cellular assays demonstrated that compound 15 (Fig. 5) was highly potent among this series of quinoline-based compounds [49].

Li et al. synthesized a new series of compounds by modifying the C-7 position of the quinoline ring system [50]. Their SAR-based study suggested that the C-7 position of quinoline-4-yl tolerates an array of substitutes, including amides, urea, cyclized urea, carba-mate, and a dimer through the urea linkage. Among this series,

NO

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O

CN

(9)

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S

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Cl

N

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NO

HN

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Cl

N

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N

N(11)

N

HN

H3CO

S

CN

Cl

N

N

N

N

(12)

N

NH2 O

CH3

(13)

Fig. (4). Quinoline-based chemical structure of MEK inhibitors.

Quinoline Based Anticancer Agents Current Medicinal Chemistry, 2011 Vol. 18, No. 1 5

compound 16 (Fig. 5) was highly potent in the enzymatic and T R-1-dependent cellular assays (IC50 were 0.043 M and 0.059 M, respectively) [50]. To improve the oral bioavailability of this mole-cule in animal model, Li et al. introduced an aminoalkoxy side chain at the C-7 position of the quinoline ring system [51]. Data obtained from their SAR-based study suggested that the substitution at the C-7 position with a bulky phenoxy group was detrimental. The authors found that compound 17 (Fig. 5) was the most potent TGF- inhibitor among this series, as it showed good oral bioavail-ability and its in vivo EC50 value (0.268 μM) was very good. The pharmacokinetic (PK) / pharmacodynamic (PD) data showed that compound 17 at 75 mg/kg twice daily delayed tumor growth statis-tically significantly in mice xenografts with human breast cancer cells [51].

QUINOLINE DERIVATIVES AS INHIBITORS OF PLATE-

LET-DERIVED GROWTH FACTOR

Platelet-derived growth factor (PDGF) is a potent mitogen for mesenchymal cells such as fibroblasts, vascular smooth muscle cells, glomerular mesangial cells, and capillary endothelial cells [52, 53]. PDGF comprises two polypeptide chains, A and B, which are present as either a homodimer (AA, BB) or a heterodimer (AB) [53]. The PDGF receptor comprises and subunits, which dimer-ize upon binding to ligand. Both PDGF receptor subunits contain a tyrosine kinase domain [54-56], which can phosphorylate their own tyrosine residues upon receptor dimerization following binding to ligand. The autophosphorylation is essential for transmission of cell growth signals [54-56], as it is in the case of many other growth factor receptors bearing tyrosine kinases, including EGFR, basic fibroblast growth factor (FGF), insulin -receptor, and stem cell factor (SCF) receptor (c-kit) [57, 58]. The overexpression of PDGF and/or its receptors often results in pathophysiological conse-quences, including neoplasia, atherosclerosis, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, glomerulosclerosis, and abnor-mal wound healing [54-56].

Inhibitors of the PDGFR tyrosine kinase activity can block its action, which would be an effective way of controlling proliferation of cancer cells with PDGF receptors overexpression [54-56]. Fol-lowing this hypothesis, Spada et al. synthesized a series of quino-line compounds to block PDGFR [59]. The authors found that 6,7-dimethoxy-3-(4-pyridinyl)quinoline (18, Fig. 6) emerged the most potent inhibitor of PDGFR (IC50, 0.1-0.8 M) among this series of compounds [59]. Dolle and co-worker synthesized and examined a series of quinoline compounds similar to those of Spada [59], among which 5,7-dimethoxy-3-(4-pyridinyl)quinoline (19, Fig. 6) was the most potent -type PDGFR inhibitor (IC50, 80 nM) [60]. In continuation of this line of work, Maguire et al. synthesized a series of substituted quinoline derivatives and examined for their activity against PDGFR tyrosine kinase using a cell-free system [61]. The authors found that the presence of 6,7-dimethoxy groups on the quinoline ring was advantageous, although it was not essential for its activity. A SAR-based study showed that a lipophilic group at-tached to the C-3 quinoline position contributed substantially to the high activity [61]. The lipophilic group comprises monocyclic aro-

matics or small alkynyl, alkenyl, and alkyl groups. Among this series of compounds, 20 (Fig. 6) was most active (IC50, 0.02-0.04

M) [61].

Kubo et al. synthesized and examined a series of 4-phenoxyquinoline derivatives, and found that (3,4-dimethoxy)-4-phenoxy-6,7-dimethoxyquinoline (21, Fig. 6) was a potent and selective inhibitor of PDGFR autophosphorylation [62]. Compound 21 effectively inhibited autophosphorylation of the PDGF -receptor in cultured rat glomerular mesangial cells (MC) bearing PDGFR (IC50, 0.1 M), although it did not inhibit autophosphoryla-tion of other growth factor receptors even at 100 mM [63]. In addi-tion, Kubo and co-workers introduced benzoyl and benzamide groups at the C-4 position of the phenoxy group on 4-phenoxyquinoline [64]. In this series, they identified two active compounds, 22 and 23 (Fig. 6) (IC50 were 0.31 and 0.050 M, re-spectively). Both compounds showed good selectivity, since neither of them inhibited EGFR autophosphorylation even at 100 M. However, compound 21 inhibited autophosphorylation of FGFR2 [64].

Shimizu et al. synthesized a series of (6,7-disubstituted-quinolin-4-yloxy-phenyl)(4-substituted-phenyl)amine derivatives and evaluated for their FGR2 inhibition by a cellular autophos-phorylation assay using OCUM-2MD3, a human scirrhous gastric carcinoma cell line [65]. Compound 24 (Fig. 6) showed decent autophosphorylation inhibitory effects on kinase insert domain receptor (KDR), c-Kit, and FGFR2. This compound also inhibited proliferation of OCUM-2MD3 cells in a dose-dependent manner. Furthermore, a study with a mouse xenograft model demonstrated that daily oral administration of compound 24 for five consecutive days showed substantial antitumor activity on the established tu-mors in a dose-dependent manner [65].

QUINOLINE-DERIVATIVES AS INHIBITORS OF KINASE

INSERT DOMAIN RECEPTOR

The receptor tyrosine kinase Kit and KDR are closely related members of the split kinase domain subfamily of tyrosine kinases, which also includes PDGFR , PDGFR , and colony stimulating factor-1 receptor (CSF-1R). Inhibition of Kit and KDR may render antitumor effects through two distinct mechanisms: a direct effect on tumor cells (Kit-inhibition mediated), and an indirect effect by the disruption of endothelial cell function (KDR-inhibition medi-ated). The combination of these two activities within a single mole-cule could be more potent against a broader range of tumor types than a molecule with inhibitory activity by a single mechanism only [66-68]. Based on this assumption, Brennan et al. synthesized a series of novel quinoline compounds linked with 2,3-substituted thiophenes, among which OSI-930 (Fig. 7) showed high potency (IC50 < 15 nM) against both Kit and KDR [69, 70]. Furthermore, a cell-based assay showed that the compound could inhibit both wild-type and V560G mutant Kit, as well as KDR and PDGFR (IC50, <100 nM). In a mouse model, OSI-930 suppressed Kit phosphory-lation by >90% over a full 24-hour period following a single oral dose of 50 mg/kg [70, 71].

N

NHNN

(14)

N

NHNN

Cl N

NHNN

NO

O

N

NHNN

ON

O

(17)(16)(15)

Fig. (5). ALK5 inhibitors derived from quinoline.

6 Current Medicinal Chemistry, 2011 Vol. 18, No. 1 Solomon and Lee

S

O

HN

OCF3

NH

N

OSI-930

Fig. (7). Chemical structure kinase insert domain receptor inhibitors derived from quinoline.

QUINOLINE DERIVATIVES AS NONRECEPTOR TYRO-

SINE KINASE INHIBITORS

Src is the prototype member of the nonreceptor tyrosine kinases family (SFKs), which includes Fyn, Lck, Lyn, Hck, Yes, Blk, and Fgr. SFKs share a common structural organization and show high similarity in the amino acid sequences of their respective ATP-binding sites. Src is involved in many cellular signaling pathways; thus, blocking Src may exhibit antitumor effects on many different tumors [72, 73]. Hence, small molecule inhibitors of Src are being actively investigated as potential anticancer agents [74-76]. Using a high throughput screening approach, Boschelli et al. identified 4-[(2,4-dichlorophenyl)amino]-6,7-dimethoxy-3-quinolinecarbonitrile (compound 25, Fig. 8) as an effective Src kinase inhibitor (IC50, 30 nM) [77]. A compound derived from 25 by replacing the C-7 methoxy group with a 3-(morpholin-4-yl)-propoxy group (com-pound 26, Fig. 8) enhanced the inhibitory effects on both Src enzy-matic activity and cell proliferation [78]. A SAR-based study showed that the aniline group at C-4, the carbonitrile group at C-3,

and the alkoxy groups at C-6 and C-7 of the quinoline were all cru-cial for potent activity [78]. Further optimization of the C-4 anilino group of compound 25 led to the development of compound 27

(Fig. 8), which contains a 2,4-dichloro-5-methoxy-aniline. Re-placement of the methoxy group at the C-7 of compound 27 (Fig. 8) with a 3-(morpholin-4-yl)propoxy group provided compound 28

(Fig. 8), which showed an increase in inhibition of both Src kinase activity and Src-mediated cell proliferation [78]. Replacement of the morpholinyl group of compound 28 with a 4-methylpiperazine group resulted in the generation of SKI-606 (Fig. 8), which showed an IC50 of 1.2 nM in the Src enzymatic assay, and an IC50 of 100 nM in the inhibition of Src-dependent cell proliferation [78]. SKI-

606 effectively inhibited tumor growth in a xenograft model with Src-transformed fibroblasts or HT29 cells. Boschelli and co-workers also reported the antiproliferative activity of SKI-606

against three different Bcr-Abl-positive leukemia cell lines, KU812, K562, and MEG-01, at IC50 ranging from 5 nM (KU812) to 20 nM (K562 and MEG-01) [79]. The authors further demonstrated that SKI-606 ablated tyrosine phosphorylation of Bcr-Abl in CML cells and fibroblast cells expressing v-Abl. In addition, SKI-606 inhibits phosphorylation of STAT5 at concentrations that inhibit prolifera-tion in CML cells. Phosphorylation of the autoactivation site of other Src family kinases Lyn and Hck was also reduced by SKI-

606. One daily oral administration of SKI-606 at 100 mg/kg for 5 days resulted in the complete regression of large K562 xenografts in nude mice [79].

In an attempt to create dual inhibitors of Src and Abl kinases, Boschelli and co-workers synthesized a series of 7-alkoxy-4-phenylamino-3-quinolinecarbonitriles. Among this series, com-pound 29 (Fig. 8) was emerged as a dual inhibitor of Src and Abl kinases at the IC50 value of 2.7 nM and 0.78 nM Src, respectively [80].

N

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O

N

H3CO

H3CO

O

HN

O

(21) (22)

(23)

N

H3CO

O

O

HN

HN

HO

(24)

Fig. (6). Quinoline-based inhibitors of PDGFR kinase.

Quinoline Based Anticancer Agents Current Medicinal Chemistry, 2011 Vol. 18, No. 1 7

Compound 30 contains the NH linkage at the C-7 position, re-sulting in a decrease in Src activity as determined by a cell-based assay (IC50, 360 nM) [81]. Other basic amines containing amino-propyl substituents at the C-7 (e.g., dimethylamine analog 31) also rendered a Src inhibitory effect (Fig. 9). Interestingly, compound 32 (Fig. 9), the methylated amino analog of 31, had a significant loss of activity as determined by both enzymatic and cell-based assays of Src (IC50 values of 2.7 μM and 300 nM, respectively) [81].

Berger et al. examined aryl and heteroaryl groups at the C-7 po-sition [82]. The authors found that introduction of 4-(4-morpholinylmethyl) phenyl group at the C-7 position (i.e., com-pound 33 in Fig. 9) showed an excellent Src inhibitory effect (IC50, 15 nM) [82]. Surprisingly, an analog of compound 33 without the C-6 methoxy group (compound 34, Fig. 9) was a more potent Src inhibitor than compound 33 (IC50, 3.3 nM). Replacement of the phenyl ring of compound 34 with a pyridinyl ring (35, Fig. 9) and

3,5-substituted thiophene analogs (36, Fig. 9) retained Src enzy-matic inhibitory activity [83, 84]. The Src inhibitory effect of com-pound 36 was further enhanced by the replacement of morpholine with 1-methylpiperazine, as their IC50 values for inhibiting Src en-zymatic activity and cell-based assays were 3.8 nM and 64 nM, respectively [84]. Boschelli and co-workers found that the 3,5-substituted furan (37, Fig. 9) at the C-7 position enhanced Src in-hibitory effect, compared to that of the 2,5-substituted furan isomer [85]. Addition of a methoxy group at the C-6 position increased the activity of the C-7, 3,5-substituted furan isomer. Compound 37 showed excellent potency in Src inhibition determined by a cell-based assay [85]. The kinase selectivity profile of compound 37

was similar to that of SK-606. When compound 37 was examined using the HT29 xenograft model at oral doses of 25, 50 and 150 mg/kg for 21 days, it provided a dose-dependent inhibition of tumor growth with no obvious toxicity [85].

N

H3CO

H3CO

CN

HN

Cl Cl

N

H3CO CN

HN

Cl Cl

ON

O

N

H3CO

H3CO

CN

HN

Cl Cl

OCH3

N

H3CO CN

HN

Cl Cl

ON

O

OCH3

(26)

(27)

(28)

N

H3CO CN

HN

Cl Cl

ON

N

OCH3

H3CSKI-606

N

H3CO CN

HN

Cl Cl

O

N

OCH3

H3C

SAR studies on

aniline group at C-4

SAR studies

on C-7 positionSAR studies

on C-7 position

SAR studies

on C-7 position

Src selectivity

SAR studies

on C-7 position

Dual activity

(25)

(29)

Fig. (8). Quinoline-based Src inhibitors (I).

8 Current Medicinal Chemistry, 2011 Vol. 18, No. 1 Solomon and Lee

To increase Src inhibitory effects, Barrios Sosa et al. introduced an ethenyl (38, Fig. 10) or ethynyl group (40, Fig. 10) at the C-7 position of the 3-quinolinecarbonitrile [86, 87]. The authors found that an addition of a C-6 methoxy group increased the inhibition of Src activity by four-fold, as compounds 39 and 41 showed IC50 values of 47 and 12 nM, respectively [86, 87]. An in vivo study showed that the Src inhibitory effect of the 7-alkynyl analog 42 (Fig. 10) was similar to that of SKI-606 [88, 89]. Since compound 42 showed very good permeability and solubility at pH 4.5 (>100 μg/ml), this compound could be used intravenously [88, 89]. Boschhelli et al. introduced a morpholinyl and piperdinyl ring sub-stitution on the C-7 alkenyl side chain (compound 43 in Fig. 10), which showed a potent inhibition on Src enzymatic activity deter-mined by cell-free and cell-based assays (IC50, 2.1 and 58 nM, re-spectively) [90].

QUINOLINE COMPOUNDS AS RET INHIBITORS

The RET (Rearranged in Transcription) protooncogene is a typical example of a gene encoding a receptor protein tyrosine kinase involved in the aetiology of human tumors [91]. Activating

RET mutations and rearrangements have been implicated in the development of sporadic and inherited forms of thyroid cancer. In papillary carcinomas, the RET/PTC oncogenes are derived from somatic chromosomal rearrangements linking the N-terminal region of an unrelated gene to the C-terminal domain of RET. As a result, a chimeric constitutively active form of RET tyrosine kinase is expressed in thyroid cells [92, 93]. In the sporadic case of me-dullary thyroid carcinoma (MTC), RET missense mutations are present at the somatic level, whereas RET mutations at the germline level are responsible for the inherited type-2 Multiple Neoplasia (MEN2) syndromes including MTC [94, 95]. RET mutants identi-fied in thyroid carcinomas are dominantly acting oncogenes that confer gain-of-function to the encoded proteins. A number of small-molecule tyrosine kinase inhibitors have been shown to inhibit the RET activity. In an effort to identify novel RET inhibitors, Ribinett et al. developed substituted 4-(3-hydroxyanilino)-quinoline com-pounds from the Src family kinase inhibitors. In that study, authors selected 27 compounds based on their potency in kinase inhibition [96]. To develop effective RET kinase inhibitors, the authors chose to carry out SAR-based optimization with quinoline scaffold mole-cules selected in the basis of their inhibition profiles on other kinase

N

H3CO CN

HN

Cl Cl

NH

N

N

OCH3

H3C

N

H3CO CN

HN

Cl Cl

NNH3C

CH3

OCH3

R

N

H3CO CN

HN

Cl Cl

OCH3

N

O N

CN

HN

Cl Cl

OCH3

N

O

N

CN

HN

Cl Cl

OCH3

N

N

S

H3C

N

CN

HN

Cl Cl

OCH3

N

N

O

H3C

H3CO

(36)

(37)

N

CN

HN

Cl Cl

OCH3

NN

N

H3C

(30)31 R = H

32 R = CH3

(33) (34)

(35)

Fig. (9). Quinoline-based Src inhibitors (II).

Quinoline Based Anticancer Agents Current Medicinal Chemistry, 2011 Vol. 18, No. 1 9

activities. The SAR-based study suggested that RET inhibitory activity is tolerable to substitution at C-6 and C-7 positions of the quinoline ring. While the substitution of quinoline ring is tolerated, the methyl sulfone appears to confer added potency and specificity, compared to the halogen substitution. Three compounds 44, 45, and

46, (Fig. 11) had Ki’s of 3, 25, and 50 nM in an in vitro kinase as-say, and a cell-based assay showed Ki’s of 300, 100, and 45 nM, respectively [96].

QUINOLINE COMPOUNDS AS PROTEASOME INHIBI-

TORS

The ubiquitin-proteasome pathway plays an important role in the degradation of cellular proteins. The proteolytic pathway in-volves two distinct steps, ubiquitination and degradation [97, 98]. The ubiquitin-proteasome pathway is indispensable in regulating cell proliferation and cell death and, thus, has been extensively studied by cancer biologists [97, 98]. The loss of balance between cell growth inducers and inhibitors leads to the deregulation of cell growth, proliferation, and survival, which may result in premature cell death, uncontrolled cell proliferation and, eventually, tumor development and progress. Thus, the inhibition of proteosome pathway is potentially a very effective target for controlling a tu-mor. Indeed, proteasome inhibitors can induce cell death rapidly and selectively in oncogene-transformed cells, but not in normal or untransformed cells [99].

Daniel et al. discovered that several organic-copper (but not zinc or nickel) compounds such as bis-8-hydroxyquinoline-copper(II) potently and specifically inhibited the chymotrypsin-like activity of proteasome in human tumor cells [100]. The inhibition of proteasome activity by organic copper compounds occurs rapidly (i.e., <15 min), followed by induction of apoptosis in tumor cells. The same treatment caused neither proteasome inhibition nor apop-tosis in normal and non-transformed human cells [100]. Further-more, Daniel et al. showed that certain quinoline compounds such as 8-hydroxyquinoline (47), clioquinol (48), and 5,7-dichloro-8-hydroxyquinoline (49) (Fig. 12) act as potent antitumor compounds by binding to endogenous copper in prostate and breast cancer cells [101]. The authors suggested that elevated levels of copper can be tumor-specific, and the use of copper chelators might be a very useful strategy for cancer therapies [101]. Adsule et al. synthesized and examined a series of Schiff bases of quinoline-2-carboxaldehyde, and found that the copper contained in these chemical complexes inhibited proteasome activity in human pros-tate cancer cells [102]. Among this series of the quinoline thiosemi-carbazone copper complex, compound 50 (Fig. 12) was the most potent in inhibiting proteosome activity in intact human prostate cancer PC-3 (IC50, 4.0 μM) and LNCaP cells (IC50, 3.2 μM). A SAR-based study suggested that the strategy adopted in modifying the parent ligand with cytotoxic thiocarbonyl side chains substan-tially enhanced the antitumor activity. Furthermore, the introduction of a thiocarbonyl group at the C-2 position in the quinoline moiety led to the generation of potent anticancer compounds upon forming

N

R CN

HN

Cl Cl

OCH3

N

38 R = H

39 R = OCH3

N

R CN

HN

Cl Cl

OCH3

N

N

R CN

HN

Cl Cl

OCH3

N

40 R = H

41 R = OCH3

(42)

N

O CN

HN

Cl Cl

OCH3

N

N(43)

Fig. (10). Quinoline-based Src inhibitors (III).

N

HN OH

N

SOHC

N

HN OH

H3CO2S

N

HN OH

H3CO2S

N

S

N

O

(44) (45) (46)

Fig. (11). RET inhibitors developed from quinoline.

10 Current Medicinal Chemistry, 2011 Vol. 18, No. 1 Solomon and Lee

a complex with copper. Finally, the authors concluded that the qui-noline thiosemicarbazone copper-complexed compound 50 could inhibit the proteasome activity and induced apoptosis as shown by PARP cleavage in the LNCaP prostate cancer cell line [102].

QUINOLINE DERIVATIVES AS TUBULIN POLYMERIZA-

TION INHIBITORS

Tubulin is the target of several drugs that interfere either posi-tively or negatively in the tubulin polymerization process. Since the disruption of microtubule dynamics results in the impediment of the cell-division process and eventually cell death, this is one of the major therapeutic strategies against human solid tumors [103]. A number of natural product compounds such as paclitaxel, epothilone A, vinblastine, combretastatin, colchicine (Fig. 13) ex-hibit anticancer properties by interfering the dynamics of tubulin polymerization and depolymerization.

Compounds binding to the colchicine domain are the subjects of intense investigation as potential anticancer therapeutics, since they can cause vascular disruption [106-106]. For example, Om-

brabulin (Sanofi-Aventis) functions as a vascular disrupting agent that can rapidly depolymerize microtubules in newly formed vascu-latures and, thus, cut off blood supply to tumors [104-107]. Analy-sis of this type of microtubule inhibitors (e.g., combretastatin, col-chicine and ombrabulin) suggests that the 3,4,5-trimethoxyphenyl/ 3,4,5-trimethoxybenzoyl and para-methoxyphenyl groups play an important role in the bioactivity. Nien et al. examined the quinoline core coupled with the 3,4,5-trimethoxybenzoyl group as tubulin polymerization inhibitors [108]. The authors found that 5-amino-6-methoxy-2-(3’,4’,5’-trimethoxybenzoyl)quinoline (51, Fig. 13) displayed potent antiproliferative activity, with IC50 values ranging from 0.2 to 0.4 nM in a diverse human cancer cell lines including the MDR-resistant cells (KB-vin 10). Compound 51 showed stronger activity against microtubule assembly than colchicine or combretastatin. Data obtained from a SAR-based study revealed that the substituted aryl group (i.e., 3’,4’,5’-trimethoxybenzoyl moiety) at C-2 and C-6 positions on the quinoline ring significantly contributed to the higher efficacy than at positions C-3, C-5, C-7, and C-8. The addition of a methoxy group at the C-6 or C-8 posi-tion of the C-2 and C-4 aroylquinolines increased potency, but an

N

OH

N

OH

Cl

Cl N

OH

Cl

I

(47) (48) (49)

NH

NNH

HS

CuCl

Cl

(50)

Fig. (12). Quinoline-based proteasome inhibitors.

H3CO

H3CO

OCH3OH

OCH3

H3CO

H3CO

OCH3NH

OCH3

COOH

HO

H3CO

H3CO

O

OCH3

H3CO

NHCOCH3

Combrestatin Ombrabulin Colchicine

N

O

NH2

H3CO

OCH3

OCH3

OCH3

(51)

O

HO

OO

S

N

R = H Epothilone A

R = CH3 Epothilone B

OR

EQa X = CH, Y = N

EQ b X = N, Y = CH

OH

O

HO

OO

OR

OH

Y

X

EQc X = CH, Y = N

EQd X = N, Y = CH

O

HO

OO OH

Y

X

Fig. (13). Tubulin polymerization inhibitors developed from quinoline.

Quinoline Based Anticancer Agents Current Medicinal Chemistry, 2011 Vol. 18, No. 1 11

additional methoxy group at the C-2 position of C-6-aroylquinoline resulted in a decrease in activity [108].

Epothilones A and B (Epo A and B) (Fig. 13) disrupt -tubulin, rendering potent antiproliferative effects on various human cancer cell lines [109]. An NMR-based study suggested that the interaction between the side-chain thiazole moiety of epothilones and the side chain of His-227 of -tubulin is essential for the antiproliferative activity. In this interaction, the thiazole ring appears to form a stacking structure with the imidazole ring of the His-227 side chain. Further, a SAR-based study on the N-positioned ring of pyridine-based analogues of Epo B (with different isomeric pyridine moie-ties in place of the natural thiazole ring) showed that its antiprolif-erative activity was similar to that of Epo B [110]. This result indi-cated that N-positioned heterocyclic has a significant influence on tubulin binding affinity of epothilones [110].

Dietrich et al. synthesized quinoline-linked Epo B analogues EQa-d (Fig. 12). All analogues have been found to interact with tubulin/microtubules and inhibit human cancer cell proliferation in vitro, albeit with different potencies (IC50 ranged 1-150 nM) [111]. The affinity of quinoline-based Epo B analogues for microtubules was dependent upon the position of the N-atom in the quinoline system. The potent inhibition of human cancer cell proliferation by epothilone analogues bearing a quinoline ring raises the possibility that it may be plausible to develop tumor-targeted prodrug by con-jugating it with tumor-targeting moieties [111].

QUINOLINE COMPOUNDS AS INHIBITORS OF HISTONE ACETYL-TRANSFERASES (HATs) AND DEACETYLASES

(HDACs)

Acetylation and deacetylation of histones play essential roles in the regulation of transcription, which are catalysed by the histone acetyl-transferases (HATs) and deacetylases (HDACs) enzyme families. The balance between acetylation and deacetylation is an important regulation mechanism of gene expression, which is di-rectly relevant to the growth, proliferation, and survival/death of a cell [112, 113]. Thus, the deregulation of HAT and HDAC is asso-ciated directly with cancer development and progress. The family of HAT enzymes may be classified into two categories based on their subcellular localization, type A (nuclear) and type B (cyto-plasmic) enzymes. The type A HATs may be grouped into several subfamilies based on the similarity of their amino acid sequences: the GNAT (GCN5-related N-acetyltransferase) family, the MYST (named after its founding members, MOZ, YBF2/SAS3, SAS2, and TIP60) family, the p300/CBP family, nuclear receptor co-activators (SRC-1, ACTR, TIF2), and other general transcription factors (e.g.,

TAFII-p250, the TFIIIC families) [114, 115]. Deregulation of GCN5/PCAF and p300 plays an important role in genetic disorders including human colorectal, breast, and pancreatic cancers [116, 117]. The cytoplasmic type B family is divided into four subgroups: the Zn-dependent classes I, II, and IV subgroups are structurally related, while the NAD-dependent deacetylases class III enzyme (sirtuins) is not.

The presence of acetyl groups at the lysine residues of HDAC neutralizes the positive charges of the histone tails, thereby decreas-ing interactions with DNA. This results in the relaxation of the chromatin and allows transcription factors access to transcription initiation sites. Since aberrant histone acetylation has been linked to malignant diseases, HDAC inhibitors have the potential of control-ling cancer by modulating transcription and inducing differentiation and apoptosis [112-117]. Thus, HDAC inhibitors may provide an exciting new class of anticancer therapeutics.

Jones et al. synthesized a series of quinoline-linked ethyl ketone derivatives to develop potential inhibitors of histone deacetylases [118]. The authors found that compound 52 (Fig. 14) possessed a significant potency as its IC50 was 140 nM on HDAC 1 in vitro, and 2 μM in a cell-based assay. Following intravenous administration in rats at 3 mg/kg, compound 52 showed a good PK and PD profile. Further investigation revealed that compound 52 was unstable in the rat plasma, as the anilide bond was readily hydrolyzed [118]. Kinzel et al. investigated aryl substituent linked imdiazole deriva-tives for their activities on inhibiting the class I histone deacetylases [119]. A SAR-based study suggested that the replacement of napthyl ring at the C-2 and C-3 positions of quinoline led to the loss of enzymatic activity in vivo. The 2-methoxyquinoline compound 53 (Fig. 14) was effective on a various HDAC isoforms, and showed a low nanomolar IC50 against the HDAC class I isoforms 1, 2, and 3. In addition, it displayed antitumor activity in the subcuta-neous HCT116 xenograft mouse model without any appreciable off-target activities [119].

Mai et al. identified two small quinoline-based molecules (54 and 55, Fig. 14) that can significantly inhibit the growth of Sac-charomyces cerevisiae in a manner similar to the GCN5 deletion mutant [120]. A histone H3 terminal tails assay in S. cerevisiae showed that the level of H3 acetylation was substantially reduced in response to compounds 54 and 55 at 0.6-1.0 mM and 1.5 mM, re-spectively. At 0.6-1.0 mM, compounds 54 and 55 effectively inhib-ited cell cycle progression, caused apoptosis, and granulocytic dif-ferentiation in human leukemia U937 cells. Using cell nuclear ex-tracts, the authors found that both these compounds could substan-tially reduce the histone HAT activity at 500 M [120]. Subse-

N CH3

O

O CH3

N

O

O CH3

N

O

OH

CH3

OH

(54)

(55) (56)

N

O

OH

OH

N

O

OH

CH3

OH

CH3

9 14(57) (58)

N

HN

O

HN

NO

O

(52)

N

NH

N OCH3

N

O O

(53)

Fig. (14). HATs and HDACs inhibitors derived from quinoline-based compounds.

12 Current Medicinal Chemistry, 2011 Vol. 18, No. 1 Solomon and Lee

quently, the authors found by a SAR-based assay that compound 56

(Fig. 14) was the most active among this series, as it could substan-tially reduce the HAT activity at 25 M, which is comparable to the efficacy of anacardic acid and curcumin [120]. To improve the efficacy of inhibiting the HAT activity further, the authors intro-duced 3-carboxy/3-carbethoxy functions at the C-3 position, and different lengths of alkyl chains (C1 to C15 carbon units) at the C-2 position of 4-hydroxyquinolines [121]. The resultant compounds displayed selective inhibition toward the members of the p300/CBP family. The authors found that 3-carboxy derivatives 57 and 58 (Fig. 14) inhibited the enzyme activities effectively; however, the corresponding ethyl esters were inactive. Further, carboxylic acid derivatives 57 and 58 caused the highest rate of apoptosis in the CD11c positive/PI negative U937 cells, perhaps due to the elevated cell permeability by the presence of a highly lipophylic alkyl chain at the C-2 position of the quinoline nucleus [121].

QUINOLINE COMPOUNDS AS P-GLYCOPROTEIN (P-GP)

MODULATORS

Overexpression of P-gp in tumor cells may cause multidrug re-sistance (MDR). P-gp acts as an energy-dependent drug efflux pump, reducing the intracellular concentration of structurally unre-lated drugs. In many tumor cells, a high level of P-gp reduces the intracellular drug concentration which, in turn, decreases the effi-cacy of a broad range of antitumor drugs [122]. Expression of P-gp may also decrease in drug absorption from the gastrointestinal tract

and increase in the elimination of drugs from the body [123, 124]. Moreover, the high expression of P-gp in endothelial cell mem-branes of the blood-brain barrier prevents the diffusion of drugs into the central nervous system [125]. Thus, P-gp plays an impor-tant role in tumor chemoresistance through alterations of anticancer drugs’ pharmacokinetics (e.g., decrease in bioavailability) and bio-distribution. Furthermore, P-gp can also act synergistically with cytochrome P450 (CYP) 3A4 to facilitate drug metabolism and elimination [126]. Modulators of P-gp function, therefore, can re-store the sensitivity of MDR cells to such drugs.

Suzuki et al. found by in vitro assays that some of the quinoline compounds synthesized in their laboratory could reverse the MDR phenotype more effectively than verapamil (a well-known anti-MDR compound) with very low toxicity. In particular, compounds MS-073 and MS-209 (Fig. 15) exhibited good pharmaceutical properties [127-130]. SAR-based analysis suggested that the com-pounds could interact with hydrogen bond donors of p170 P-gp via

-hydrogen- interactions since two aryl rings in the hydrophobic moiety deviate from a common plane [128]. Other major structural features which influence the MDR-reversing activities of these compounds are a quinoline nitrogen atom and a basic nitrogen atom in piperazine. The authors also found that the distance between the hydrophobic moiety and the basic nitrogen atom (an atom con-nected to 2-hydroxypropoxyquinoline) must be at least 5 Å [128]. An in vitro study showed that 1.0-10 M MS-209 completely re-versed cells’ drug resistance against vincristine (VCR) in multidrug-resistant variants of mouse leukemia P388 and human

N

O

HN

NH

ON

H3CO

H3CO

OCH3

OCH3

N

O

HN

NH

ON

H3CO

H3CO

N

O

HN

NH

O

H3CO

H3CON

N

N

O

HN

NH

O

H3CO

H3CON

N

OCH3

OCH3

XR9576

(59) (60)

(61)

N

ON

OH

N

O

N

ON

OH

N

MS-209 MS-073

Fig. (15). P-glycoprotein modulators derived from quinoline molecules.

Quinoline Based Anticancer Agents Current Medicinal Chemistry, 2011 Vol. 18, No. 1 13

leukemia K562 cell lines. Furthermore, MS-209 at 1.0-10 M also completely reversed resistance against adriamycin in P388/VCR (vincristine resistant cells), K562/VCR cells, and K562/ADM (adriamycin resistant) cells. MS-209 enhanced the chemotherapeu-tic effect of vincristine in P388/VCR-bearing mice [130]. When MS-209 was given p.o. at 80 mg/kg twice a day (total dose, 160 mg/kg per day) along with 100 mg/kg vincristine, a treated/control (T/C) value of 155% was obtained. MS-209 also enhanced the chemotherapeutic effect of adriamycin in P388/ADM-bearing mice. The enhancement of drug efficacy by MS-209 is due to the inacti-vation of P-gp, since this quinoline-based compound could effi-ciently inhibit [3H]-azidopine photolabeling of P-gp. Moreover, the level of adriamycin accumulation in K562/ADM cells was higher in the cells treated with MS-209 than verapamil treated positive con-trol [130].

An in vitro study showed that 0.1 M MS-073 (Fig. 15) could completely reverse cells’ resistance to VCR in the VCR-resistant P388 cells [131]. The compound also reversed cell’s resistance to adriamycin, etoposide, and actinomycin D in the K562 (K562/ADM), A2780 (ADM-resistant human ovarian carcinoma cell line), and KB cells (colchicine-resistant human cell line). MS-

073 administered i.p. daily for 5 days along with VCR enhanced the chemotherapeutic effect of VCR in mice bearing P388 cells. In-creases in life span of 19-50% were obtained by the combination of 100 mg/kg of VCR with 3-100 mg/kg of MS-073, as compared to the control. Data obtained from both in vitro and in vivo studies showed that the ability of MS-073 to reverse MDR was remarkably higher than verapamil, even at low doses [131].

Roe et al. synthesized and examined a series of novel modula-tors based on quinoline-linked anthranilamide nucleus for their anticancer activities, which led to the discovery of XR9576 (Fig. 15) [132]. In vitro evaluation of XR9576 using a panel of human (H69/LX4, 2780AD) and murine (EMT6 AR1.0, MC26) MDR cell lines demonstrated that it could not only potentiate the cytotoxicity of several drugs including doxorubicin, paclitaxel, etoposide, and vincristine, but also completely reverse drug resistance at 25-80 nM concentration [133, 134]. The reverse of the drug resistance by XR9576 is due to the inactivation of P-gp, since it inhibits P-gp-mediated efflux of [3H]daunorubicin and rhodamine 123. Although the inhibition of P-gp was reversible, the drug effects persisted for >22 h after its removal. This is in contrast to P-gp substrates such as cyclosporin A and verapamil, which lose their activity within 60 min, suggesting that XR9576 is not transported by P-gp [135]. Also, XR9576 was a potent inhibitor of photoaffinity labeling of P-gp by [3H]azidopine; thus, this compound may directly interact with P-gp. In mice bearing the intrinsically drug-resistant MC26 colon tumors, co-administration of XR9576 potentiated the antitumor activity of doxorubicin without significantly increasing toxicity. In this case, the maximum potentiation was observed at 2.5– 4.0 mg/kg, either i.v. or p.o [136]. In addition, co-administration of XR9576 (6 –12 mg/kg p.o.) fully restored the antitumor activity of paclitaxel, etoposide, and vincristine against two highly multidrug-resistant human tumor xenografts (2780AD, H69/LX4) in nude mice. Importantly, all of these combinational treatments appeared to be well tolerated [135, 136]. Furthermore, Walker et al. found that the inhibition of P-gp function by XR9576 in a solid tumor

could restore the drug efficacy of vinblastine and doxorubicin [137].

Labrie et al. synthesized XR9576 analogs by replacing the aromatic spacer group between nitrogen atoms (N1 and N2) with a flexible alkyl chain of 2 to 6 carbon atoms [138]. SAR-based analy-sis suggested that the flexibility of the linker between N1 and N2 might be important for the inhibitory activity. In addition, the dis-tance between N1 and N2 may also influence the activity of the drug. However, compound 59 (Fig. 15) was less cytotoxic than verapamil or XR9576. In addition, compound 59 has a different CYP inhibition profile from that of XR9576 [138].

To optimize anti-P-gp activity of compound 59, Labrie et al. ri-gidified the spacer group between N1 and N2 on the aromatic linker [139]. The authors introduced R or S pyrrolidinyl group and cyclo-hexyl group in the place of arylpiperazinyl (XR9576) and ethyl linker (59), respectively. A SAR-based study suggested that the introduction of cyclohexyl group did not affect P-gp activity. The presence of a chiral center introduced via R or S pyrrolidiones also did not exhibit any significant effect on the inhibitory activity. However, a compound bearing a cyclohexyl group (instead of an ethyl group) as linker was more active than verapamil. These data suggest that active anthranilamides require a high level of flexibility between N1 and N2 and, possibly, bring the basic amine group to a proper conformation to bind efficiently to P-gp [139]. This was expected because it is a common feature for the MDR modulators, which are often flexible molecules that can adapt the groups inter-acting with the recognition site in a variety of binding modes [139]. Furthermore, the addition of two methoxy groups to the an-thralinidyl moiety increased the efficacy of compound 60 (Fig. 15) by 200%. This data suggests that the high efficacy of compound 61 (Fig. 15) is probably due to the presence of an additional acceptor group on the anthralinidyl moiety. Alternatively, it could be due to an increase in the H-bond acceptor strength of the carbonyl-group para to the methoxy group. The presence of the methoxy groups may also increase the electron density of the aromatic ring system, enhancing pi/pi interactions. The most potent P-gp modulator in this series was compound 61, which was as active as XR957618 and 18 times more active than verapamil. Compound 61 (Fig. 15) inhibited CYP3A4 and a few other CYPs at low nanomolar concen-trations. There are also increasing lines of evidence that the pres-ence of intratumoral enzymes such as CYP3A4, which is known to co-localize with P-gp, may play an important role in the develop-ment of cancer chemoresistance [138, 139].

QUINOLINE COMPOUNDS AS DNA INTERCALATING

ANTICANCER AGENTS

The lowest possible association constant is preferred when in-tercalative binding to DNA is necessary for antitumor activity of quinoline compounds [140-142]. This is because compounds with a high proportion of unbound fraction available at the equilibrium can permit better distributions of the drug in vivo. Drugs with this prop-erty generally show a broader spectrum of activity than structurally related compounds with high binding constants [143]. A systematic study of the isomeric phenylquinoline-8-carboxamides demon-strated that some of those compounds possessed antitumor activities

N

ONH

NH3C

CH3

(62)

N

NNH

NH3C

CH3

OH

(63)

Fig. (16). DNA intercalating agents derived from quinoline molecules.

14 Current Medicinal Chemistry, 2011 Vol. 18, No. 1 Solomon and Lee

by intercalating with DNA, which was critically dependent upon the appended phenyl ring [143]. In particular, the 2-isomer N-[(2-dimethylamino)ethyl]-2-phenylquinoline-8-carboxamide (62, Fig. 16) possessed excellent activities against a broad range of cancer cell lines [143]. In continuation of this approach, Atwell et al. syn-thesized a series of similar compounds, in which they introduced various substitutes on the phenyl ring system [144]. Among this series, compound 63 (Fig. 16) was superior to the parent compound, rendering approximately 50% cure rates in leukemia and solid tu-mor models [144].

QUINOLINE COMPOUNDS AS DNA ALKYLATING ANTI-

CANCER AGENTS

DNA alkylating agents have been widely used in cancer chemo-therapy [145-147]. However, these agents have several drawbacks, including lack of specificity to tumor cells, high chemical reactiv-ity, and induction of bone marrow toxicity [148-150]. To overcome some of these problems, DNA-directed alkylating agents and pro-drug approaches have been developed [145]. In these approaches, alkylating pharmacophores (such as the N-mustard residue) are linked to molecules with high DNA affinity (such as DNA interca-lating agents or DNA minor groove binder) [151-153]. Based on the information obtained from a preliminary approach, Kakadiya et al. synthesized a new series of N-mustard-quinoline conjugates, in which quinoline acts as a DNA minor-groove binding agent [154]. SAR-based studies showed that conjugates with hydrazinecarbox-amide linkers (64, Fig. 17) were generally more cytotoxic than those bearing a urea linker (65, Fig. 17). In particular, compounds 64a, 64b, 65a, and 65b (Fig. 17) showed high cytotoxicity to solid tumors, including H1299 (human non-small cell lung cancer cell line), CL 1-0 and CL 1-5 (lung adenocarcinoma), PC-3 (prostate cancer), and MCF7 (breast cancer). Importantly, nude mice bearing human breast tumor cells were completely tumor remission by treatment of these compounds [154]. The newly synthesized N-

mustards were chemically and metabolically stable in the rat plasma. A study by alkaline agarose gel shift showed that all of the active compounds could interact with DNA and form interstrand cross-links, which could not be separated into single strand under alkaline conditions. The cross-linking ability of these compounds was comparable to melphalan (a positive control).

King et al. studied bifunctional cross-linking activity of 3,6-diaziridinyl-2,5-bis(carboethoxyamino)-1,4-benroquinone (AZQ) on isolated calf thymus DNA, by using ethidium bromide fluores-cence assay. The authors suggested that AZQ produced covalently cross-linked DNA only in the presence of a reducing agent, NaBH, NADH or NADPH. The AZQ-induced DNA cross-linking was pH dependent, with lower pH favoring for more effective cross-linking [155]. Li et al. synthesized a series of potential DNA bisintercala-tors by linking an 8-hydroxy-quinoline molecule to the 6-CH2OH group of glucose and connecting the 1-OH group of glucose with various linkers such as quinol, glycol, and triethylene glycol [156]. Among this series, compound 66 (Fig. 17) showed significant activ-ity against the MDA-MB231 breast cancer cells. Binding assays suggested that compound 66 bound to calf thymus DNA by interca-lation. The glucose group regulates the interaction between the compound and DNA duplex [156].

QUINOLINE BASED ANTICANCER MOLECULES WHOSE MODE OF ACTIONS HAVE NOT YET BEEN WELL

CHARACTERIZED

Kraus and co-workers screened a chemical library containing a series of bis-8-hydroxyquinoline-substituted benzylamines for bio-activity using the KB3-1 (human mouth epidermal carcinoma) cell line [157]. The authors found that compounds 67 and 68 (Fig. 18) were particularly potent as their CC50 (50% cytotoxic concentra-tion) values were 2.6 and 1.3 nM, respectively [157]. Subsequently, the authors found that the two compounds were very effective on many different cell lines but not all, including PC3 (prostate cancer

N

HN NH

ON

Cl

ClHN N

H

ON

Cl

Cl

HN

N R1

R2R2

R1

(65)(64)

65a R1 = CH3 R2 = H

65b R1 = 3-CH3O-C6H4 R2 = 6-CH3O

64a R1 = CH3 R2 = 6,7-(OCH2O)

64b R1 = CH3 R2 = 6-N(CH3)2

OHO

HOOH

O

O

N

OOH

OHHO

O

O

N

(66)

Fig. (17). DNA alkylating anticancer agents derived from quinoline molecules.

Quinoline Based Anticancer Agents Current Medicinal Chemistry, 2011 Vol. 18, No. 1 15

cell line) and SF268 (neuroblastoma cell line). The antitumor activ-ity of 8-hydroxyquinoline substituted arylamines appears to be strongly correlated with their ability to generate relatively stable and moderately reactive quinone methide intermediates that can react with thiols, but not with DNA (probably due to their electro-philicity) [158].

Kim et al. screened a library of 11,000 small molecules to iden-tify an anticancer agent effective on leukemia [159]. The authors found that 2-amino-N-quinoline-8-yl-benzenesulfonamide (69, Fig. 18) was a potent cytotoxic compound that could induce cell cycle arrest and apoptosis. Treatment of Jurkat T cells with compound 69 increased the levels of cyclin B1 and Cdc2 phosphorylation, result-ing in cell cycle arrest at G2/M. The activation of apoptosis by compound 69 was caspase-dependent since it was blocked by z-VAD-fmk, a pan-caspase inhibitor [159].

We have synthesized hybrid compounds by linking the main structural unit of the 4-piperazinylquinoline ring system with an isatin ring (70, Fig. 18) by a Mannich base reaction, and examined their cytotoxic effects on two human breast tumor and two match-ing non-cancer cell lines [160]. A SAR-based study suggested that a hydrophobic substitution (chloro and bromo) on the isatin ring sys-tem was favorable for enhancing cytotoxicity. However, the com-pound derived from bioisoteric replacement of the 7-chloro group with 7-trifluoromethyl substitution on the 4-piperazinylquinoline ring system was not favorable for the enhancement of cytotoxicity on the breast cancer cells examined. Data obtained from flow cy-tometry suggested that this class of compounds induced cell death by apoptosis [160]. We also utilized the repositioning concept to synthesize new molecules to further optimize chloroquine-based anticancer agents, in which we selectively modified the lateral side chain of diethyl amino functionality (71, Fig. 18) with a variety of heterocyclic ring substitutes, including piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, substituted piperazinyl, and isatin [161]. SAR-based analysis suggested that compounds derived from the 7-trifluoromethyl-4-aminoquinoline lateral side chain substituted series showed less antiproliferative activity than the corresponding 7-Cl derivatives [161].

Chang et al. synthesized and evaluated antiproliferative activi-ties of styrylquinoline (72) and 2-furanylvinylquinoline derivatives (73, Fig. 18) [162]. Their SAR-based studies suggested that intro-duction of an electron-donor group such as -OH or an electron withdrawing group such as -CN, -F, and -NO2 at the 2-styryl moiety of compound 72 did not improve antiproliferative activity. Simi-larly, replacement of the phenyl ring with its heterocyclic isosteric isomers such as a pyridine or furan ring proved to be no improve-ment in activity, either. However, replacement of the phenyl ring with a 5-nitrofuran-2-yl group significantly enhanced antiprolifera-tive activity; particularly, (E)-2-(2-(5-nitrofuran-2-yl)vinyl) quinolin-8-ol (73) exhibited a very strong antiproliferative effect on MCF7 (Breast), NCI-H460 (Lung), and SF-268 (CNS) cancer cell lines. Furthermore, compound 73 induced cell cycle arrest at S phase in LNCaP and PC3 cells, eventually leading to apoptosis [162].

Zhao et al. synthesized a series of 4-anilino-2-phenylquinoline derivatives, and examined their anticancer activities [163]. The authors found that 4-(4-acetylphenylamino)-6-methoxy-2-phenylquinoline (74), its oxime 75, and methyloxime 76 (Fig. 18) exhibited significant cytotoxicity against all 60 cancer cell lines examined, with mean GI50 values of 3.89, 3.02, and 3.89 μM, re-spectively. A SAR-based study suggested that introduction of a free carboxylic acid at the C-3 position of quinoline ring was unfavor-able for anticancer activity. The steric hindrance exerted by 3-carboxylate may prevent the adjacent phenyl ring reclining coplanar with quinoline, which leads to very low cytotoxicity. The compara-ble cytotoxicity of oxime 75, methyloxime 76, and the ketone pre-cursor 74 may imply that a hydrogen-bonding accepting group at

the C-4 position of the 4-anilino-moiety is crucial for their cytotox-icity. Among this series, compound 74 was especially active against the proliferation of several tumor cell lines, including NCI-H226 (non-small cell lung cancer), MDA-MB-231 (breast cancer), and SF-295 (CNS cancer) with GI50 values of 0.94, 0.04, and <0.01 μM, respectively [163]. To further improve their drugability, the same group synthesized two additional sets of compounds by introducing -OCH3 and -OH functionalities at the C-6 and C-8 positions of the quinoline ring system [164]. The antiproliferative activity of 4’-COCH3-substituted derivatives decreased in the order 6-OMe > 8-OMe > 8-OH, suggesting that the substitution at the quinoline ring is crucial for their activities. For 3’-COCH3 derivatives, the antipro-liferative activity of 8-OH is more potent than its 8-OMe counter-part, suggesting that one H-bond donor substitute is more favorable over one H-bond acceptor group. Among this series, compound 77 was especially active against the proliferation of certain solid can-cer cells, including HCT-116 (colon cancer), MCF7, and MDA-MB-435 (breast cancer) with GI50 values of 0.07, <0.01, and <0.01

M, respectively. Data obtained from flow cytometry revealed that growth inhibition by compound 77 (Fig. 18) was due to cell cycle arrest in S phase [164].

Through SAR-based optimization, Tzeng and co-workers syn-thesized a series of 2-(furan-2-yl)-4-phenylamino)quinoline deriva-tives, in which the C-2 phenyl ring was replaced with a furan-2-yl ring [165]. The authors found that the 2-(furan-2-yl)-4-phenylamino)quinoline isomer (compound 78, Fig. 18) was active as its mean GI50 was 4.36 μM. The authors also found that a mole-cule bearing a para-COCH3 substituent was more active than its meta-substituted counterpart. However, the electron-donor -CH3O substitute was preferred at the meta-position. The resultant com-pound 79 was most effective with the mean GI50 value of 3.05 μM [165].

Shi et al. synthesized a series of quinoline compounds and ex-amined their anticancer activity using the T47D breast cancer cell line [166]. The authors found that the compound N-(furan-2-ylmethyl)-6-methoxy-4-methyl-5-(3-(trifluoromethyl)phenoxy) quinolin-8-amine (80, Fig. 18) showed IC50 of 16 ± 3 nM. The ab-sence of asymmetric center in this molecule alleviated the chiral synthesis and purification of enantiomers for bioevaluation [166].

Somvanshi et al. synthesized a series of 2,4-dichloro-6 meth-ylquinoline derivatives (81, Fig. 18), and evaluated for their anti-cancer activities using oral carcinoma cells [167]. Data from SAR-based studies suggested that an aliphatic group at the C-7 position and chlorine at C-2 and C-4 positions were important for cytotoxic activity of eukaryotic cells [167].

Hurren and co-workers examined a series of quinolines and quinoline-like molecules for their anticancer activity, which led to the identification of an active novel diquinoline molecule, 1-methyl-2-[3-(1-methyl-1,2-dihydroquinolin-2-yliden)prop-1-enyl]quinolinium iodide (82, Fig. 18) [168]. Compound 82 induced cell death in leukemia, myeloma, and solid tumor cell lines with LD50 (50% lethal dose) at a sub-micromolar range. Moreover, com-pound 82 induced cell death in primary acute myeloid leukemia (AML) cells, preferentially over normal hematopoietic cells. Com-pound 82 caused tumor cell death by autophagy in xenograft leu-kemic mice, resulting in a delay of tumor progression [168].

Ashaks and co-workers synthesized and examined a series of metal quinoline-8-selenolates for their cytotoxic effects on HT-1080, MG-22A, B16, Neuro 2A tumor cell lines, which led to the discovery of mercury quinoline-8-selenolate (83, Fig. 18) being the most active compound among this series [169]. Further, this group synthesized a series of quinoline disulfides, with the aim of decreas-ing side effects and increasing selectivity [170]. Among this series, compound di(8-quinolyl) disulfide (84, Fig. 18) was most effective (LC50 0.3-0.4 μg/ml) on the HT-1080 (human fibrosarcoma) and MG-22A (mouse hepatoma) cell lines [170].

16 Current Medicinal Chemistry, 2011 Vol. 18, No. 1 Solomon and Lee

N

OH

N

N

HO

R

67 R1 = CH3

68 R2 = CF3

N

HNS

O

O

H2N

(69)

NR

N

N

N

X

O

R1

R = Cl, CF3 X = O, N-NH-C=S-NH2

N

HN N

R

R2

R1

R = Cl, CF3

(70) (71)

N

CH3O

H3CO

HN

F3C

O

(80)

N

H3CO

HN

CH3

X

74 X = O

75 X = N-OH

76 X = N-OCH3

N

HN

78 R = p-COCH3

79 R = m-OCH3

O

R

N

HN

O

CH3

OH

(77)

N

OHR

N

OH

O NO2

(72)

(73)

NN

I-

+

(82)

N

H3C

Cl

Cl

(81)

NN

SeSeHg

(83)

N

NHO

N

N

NHO

NH

O

O

N

NHO

NH

O

O

H3C

(87) (88) (89)

N

S

N

S

N

S

N

S

H3CO

H3CO

(84) (85)

N

CH3

S

3

Rh +

(86)

Fig. (18). Diverse quinoline compounds possessing anticancer activities.

Quinoline Based Anticancer Agents Current Medicinal Chemistry, 2011 Vol. 18, No. 1 17

To improve selectivity of the compound, the same group intro-duced one or two electron donors or acceptors to the quinoline ring system [171]. A SAR-based study showed that the nature of substi-tutes and its positions in the quinoline ring markedly affected the antitumor activity of di(8-quinolyl) disulfides. These authors found that the greatest cytotoxicity in the series of methyl derivatives was shown by the 7-, 6-, and 3- isomers on HT-1080 (human fibrosar-coma) and MG-22A (mouse hepatoma) tumor cell lines, while the 2-methyl derivatives generally were not effective [171]. High cyto-toxicity was also shown (LC50 <1 μg/ml) by other 7-substituted compounds (-Cl, -PhO, -PhS). Unfortunately, however, these com-pounds also showed high toxicity on normal NIH 3Y3 mouse em-bryonic fibroblasts [171]. Similarly, the authors found that the se-ries of 5-substituted compounds (-NH2, -Cl, -OMe, -NO2) were highly cytotoxic to both cancer and non-cancer cells [171]. The 6-methoxy substituted quinoline (85, Fig. 18) showed higher cytotox-icity to tumor cells than normal fibroblasts at low concentrations (LC50 100 μg/ml with a corresponding LD50 of 874 mg/kg) [171]. To further improve efficacy and specificity, this group synthesized and examined a series of metal 4-methyl-8-quinolinethiolates [172]. They found that rhodium 4-methyl-8-quinolinethiolate (86, Fig. 18) was 46 times less toxic than unsubstituted 8-quinolinethiolate, with comparable antitumor activity on the MG-22A tumor cell line (LC50 2 μg/ml) [172].

Zhang et al. designed and synthesized novel ligands, N-(8-quinolyl)-2-pyridinecarboxamide (87), N-(8-quinolyl)glycine-N’-Boccarboxamide (88) and N-(8-quinolyl)-L-alanine-N’-Boc-carboxamide (89) (Fig. 18) [173]. In this series, the amino-quinoline moiety was condensed with either picolinic acid, amino acids glycine, or L-alanine. The authors examined the chelating behavior of these compounds to Cu (II) in order to reveal the ligand influence on the geometry and, subsequently, the biological activity [174]. A series of experiments with several different cell lines showed that the copper complexed compound 87 showed the most potent antiproliferative activity [174].

We previously found that quinoline compounds could sensitize cancer cell killing by other anticancer therapeutics [10, 175, 176]. For example, the combination of 10 μM chloroquine with the Akt1/2 inhibitor 1,3-Dihydro-1-(1-((4-(6-phenyl-1H-imidazo[4,5-g]quinoxalin-7-yl)phenyl)methyl)-4-piperidinyl)-2H-benzimidazol-2-one killed cancer cells 10-120 times more effectively than non-cancer cells [175]. In addition, certain chloroquine analogs (e.g., N'-(7-Fluoro-quinolin-4-yl)-N,N-dimethyl-ethane-1,2-diamine) highly sensitized cell killing effects by other Akt inhibtors in a cancer-specific manner [176]. Together, these data show the tremendous potential of quinoline compounds in combinational therapies.

FUTURE DIRECTIONS

As described above, quinoline compounds show antiprolifera-tive activity on a broad spectrum of different tumors, as they can target many different signaling and enzymatic pathways. Theoreti-cally, quinoline-based inhibitors against any of these pathways can potentially be effective anticancer drugs. Furthermore, several re-searchers have shown that quinoline-based compounds have the potential of being a very efficient drug with differential cell killing effects against malignant tumors. This important property of quino-line can be utilized further by studying the mechanism of action for each promising quinoline compound. In particular, selectively tar-geting cancer-specific signaling or enzymatic pathways by a quino-line compound will be extremely important for the development of effective and safe anticancer therapeutics. To further optimize the full potential of quinoline compounds, the SAR-based study will likely continue to play an important role. It is highly likely that optimized quinoline compounds with excellent potency and little side effects will continue to be created. Some of these quinoline compounds will undoubtedly be used as first line cancer therapeutic

agents in the near future. Furthermore, since quinoline compounds can substantially sensitize cell killing by other anticancer drugs in a cancer-specific manner, they can be very effective sensitizers for conventional cancer therapeutics.

ACKNOWLEDGEMENTS

This work was supported by funds from the Canadian Cancer Society Research Institute (CCSRI) and Natural Sciences and Engi-neering Research Council of Canada (NSERC) to H.L. VRS thanks the Ontario Ministry of Research & Innovation for a Postdoctoral Fellowship.

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