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RESEARCH POSTER PRESENTATION DESIGN © 2011
www.PosterPresentations.com
Towards the Synthesis and Biological Evaluation of 2nd-Generation Taxoid SB-T-1216
Paclitaxel and docetaxel are among the most widely used chemotherapeutic
agents for the treatment of a variety of cancers, such as breast, ovarian, and
non-small cell lung cancer. However, these taxoids do not show efficacy
against drug-resistant tumors. With the development of the β-Lactam Synthon
Method (β-LSM), a series of new generation taxoids were prepared, which
exhibit at least 2 orders of magnitude greater activity against a number of
drug-resistant cell lines. SB-T-1216 is one such highly potent 2nd-generation
taxoid. In order to synthesize this drug, enantiopure β-lactam was prepared via
the chiral ester-enolate imine cyclocondensation and the Staudinger [2+2]
ketene-imine cycloaddition, followed by enzymatic kinetic resolution. SB-T-
1216 is subsequently obtained by the ring-opening coupling of this
enantiopure β-lactam to a modified baccatan, followed by deprotection. The
synthesis of SB-T-1216 will be presented. This material will be used to further
ongoing research efforts towards understanding the detailed mechanism of
action of this next generation taxoid.
1.0 Introduction
1.1 Cancer
2.0 Synthesis of Enantiopure β-lactam
2.1 Staudinger [2+2] Ketene-Imine Cycloaddition Followed by Enzymatic Kinetic Resolution7-9
Modification of the C-10 Position: C-7 protection followed by C-10 acylation
3.0 Synthesis of SB-T-121614
4.0 Biological Evaluation of SB-T-121615
6.0 References1. Malumbres, M., Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm. Nat. Rev. Cancer. 2009, 9, 153-166.
2. Siegel, R., Ward, E., Brawley, O., Jemal, A., Cancer statistics, 2011. CA Cancer J Clin. 2011, 61, 212-236.
3. Rowinsky, E., Donehower, R. Paclitaxel (Taxol). J. Med. 1995, 332, 1004-1014.
4. Ojima, I., Miller, M. Chemistry and Chemical Biology of Taxane Anticancer Agents. The Chem. Rec. 2001, 1, 195-211.
5. Higgins, CF., Linton, KJ. The ATP switch model for ABC transporters. Nat. Struct. Mol. Biol., 2004, 11(10), 918-26.
6. Cancer multidrug resistance. Nat. Biotechnol. 1999, 17, 94–95.
7. Palomo, C., Jesus, M., Inaki, A., Oiarbide, G.M. Assymetric Synthesis of β-lactams by Staudinger Ketene-Imine Cycloaddition Reactions. J. Org. Chem., 1999, 1999(12),
3223-3235.
8. Brieva, R., Crich, J.Z., Sih, C., Chemoenzymatic Synthesis of the C-13 Side Chain of Taxol: Optically Active-3-Hydroxy-4-Phenyl β-lactam Derivatives. J. Org. Chem.,
1993, 58, 1069-1075.
9. Ojima, I., Recent Advances in the β-Lactam Synthon Method. Acc. Chem. Res. 1995, 28, 383-389.
10. Sharpless, B., Kold, H., VanNieuwenhze, M. Catalytic Asymmetric Dihydroxylation. Chem. Rev. 1994, 94, 2483-2547.
11. King, B., Sharpless, B. An efficient synthesis of enantiomerically pure trans-2-phenylcyclohexanol. Tetrahedron Lett. 1994, 35, 5611-5612.
12. Ojima, I., Slater, J., Kuduk, S., Takeuchi, C., Gimi, R., Sun, C., Park, Y., Pera, P., Veith, J., Bernacki, R. Syntheses and Structure-Activity Relationships of Taxoids Derived
from 14-β- Hydroxy-10-deacetylbaccatin III. J. Med. Chem. 1997, 40, 267-278.
13. Ojima, I., Habus, I., Zhao, M., Zucco, M., Park, Y., Sun, C., Brigaud, T. New and Efficient Approaches to the Semisynthesis of Taxol and its C-13 Chain Analogs by Means
of the β-Lactam Synthon Method. Tetrahedron. 1992, 4, 6985-7012.
14. Ojima, I., Slater, J., Michaud, E., Kuduk, S., Bounaud, P., Vrignaud, P., Bissery, M., Veith, J., Pera, P., Bernacki, R. Syntheses and Structure-Activity Relationships of the
Second-Generation Antitumor Taxoids: Exceptional Activity against Drug-Resistant Cancer Cells. J. Med. Chem. 1996, 39, 3889-3896.
15. Ojima, I., Kovář, J., Ehrlichová, M., Šmejkalová, B., Zanardi, I., Gut, I. Comparison of Cell Death-inducing Effect of Novel Taxane SB-T-1216 and Paclitaxel in Breast
Cancer Cells. Anticancer Res., 2009, 29(8), 2951-2960.
16. Ojima, I., Jaracz, S., Chen, J., Kuznetsova, L. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg. Med. Chem., 2005, 13(2005), 5043–5054.
7.0 Acknowledgements
-This research was supported by a grant from the
National Cancer Institute (CA 103314 to I.O.)
-The authors would also like to thank URECA for
allowing them the opportunity to present this
research.
Cancer is a complex class of diseases that results from the loss of
mechanisms that regulate cellular proliferation. Tumorous cells accumulate a
number of mutations and defective modifications that results in constitutive
mitogenic signaling. Furthermore, these cells respond abnormally to
corrective, anti-mitogenic efforts.1 The ramification of this synergistic interplay
is the rapid, unscheduled proliferation of these cells and the subsequent
formation of a tumor. As the second leading cause of death within the United
States, cancer continues to remain a major problem in public healthcare.2 It is
therefore imperative that efficient pharmaceutical drugs are created for the
treatment of its various forms.
(1) Department of Chemistry, State University of New York at Stony Brook, Stony Brook, NY 11794-3400
(2) ICB&DD, State University of New York at Stony Brook, Stony Brook, NY 11794-3400.
Adele Whaley1, Anushree Kamath1,2, Jacob Vineberg1, Iwao Ojima1,2
1.2 Paclitaxel and Docetaxel- Mechanism of Action
1.3 Expression of MDR Phenotypes
Paclitaxel and docetaxel are categorized as microtubule-stabilizing anticancer
agents. These taxoids bind to the β-tubulin subunit of the tubulin heterodimer,
the primary constituent of cellular microtubules, and accelerates its
polymerization. Microtubules play a critical role in the formation of the mitotic
spindle during cell division, and are also important in many vital interphase
activities.3 In the presence of these abnormally stable microtubules, mitotic
arrest is induced, eventually leading to apoptosis of the cancerous cells.4
Paclitaxel and docetaxel are relatively ineffective against cancerous cell lines
expressing multidrug resistant (MDR) phenotypes. The principle mechanism
behind MDR cancers has been largely attributed to the presence of two
molecular pumps in tumor cell membranes that actively expel cytotoxic agents
from their interior; the P-glycoprotein pump (Pgp), which is an effective ATP-
binding cassette (ABC) transporter, and the multidrug resistance-associated
protein (MDP).5,6 Because the new generation taxoids are not effective
substrates for the Pgp pump, they are more effective at treating tumors that
express the MDR phenotype.
2.2 Chiral Ester-Enolate Imine Cyclocondensation10-13
Modification of the C-13 Position: Ojima-Holton coupling
Effect of paclitaxel and SB-T-1216 at death inducing
concentrations on the DNA histogram of MDA-MB-435 and
NCI/ADR-RES cells after a 24 h incubation period. The cells
were stained with propidium iodide and analyzed by flow
cytometry. 15
-Enantiopure β-lactam was prepared in good yield via the chiral ester enolate-imine
cyclocondensation and the Staudinger [2+2] ketene-imine cycloaddition.
-SB-T-1216 will be obtained in the ring opening coupling of this enantiopure β-lactam to a modified
baccatan followed by deprotection
-SB-T-1216 is a potent second generation taxoid that is more effective than paclitaxel, especially
against breast cancer cell lines expressing MDR phenotypes. Like its parent taxoid, SB-T-1216 is a
microtubule stabilizing agent that promotes the formation of microtubule bundles in interphase cells.
-Due to its increased cytotoxicity, SB-T-1216 has been shown to induce cell death at lower
concentrations than its parent taxoid, especially in the case of drug-resistant cell lines. While the IC50
(concentration of taxoid resulting in 50% of living cells in comparison with the control) of SB-T-1216 in
the drug-sensitive human breast cancer cell line MDA-MB-435 was 0.6 nM versus 1 nM for paclitaxel,
its IC50 in the drug-resistant human breast cancer cell line NCI/ADR-RES was 1.8 nM versus 300 nM
for paclitaxel. 15,16
Effect of paclitaxel and SB-T-1216 on the formation of
interphase microtubule bundles after a 24 h incubation period
in the drug sensitive human breast cancer cell line MDA-MB-
435 and the drug resistant human breast cancer cell line
NCI/ADR-RES. Microtubules stained with Cy3-conjugated
anti-tubulin antibody (red). Cell nuclei stained with DAPI
(blue).15
5.0 Conclusions
Effect of SB-T-1216 on the growth and survival of MDA-MB-435 and NCI/ADR-RES cells after a 96 h incubation period. Control cells (C)
were inoculated without SB-T-1216. The cells were seeded at 1 x 104 cells/100 μl of medium in the well. The dotted line represents the
number of cells of the inoculum. Each point represents the mean of 8 separate cultures SEM. 15