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UTS:SCIENCE UTS CRICOS PROVIDER CODE: 00099F
A/Prof Alison Ung Natural products-led drug discovery
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Who we Are Team AMaM Advanced
Molecules and Materials
Multidisciplinary
team of Chemists,
Physicists and
Materials Scientists
Tristan Rawling
Drug Discovery from Natural Product Derived Scaffolds
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Working with Johnson & Johnson Research Pty Limited (JJR) (1994-2007)
Synthesis of novel compounds from natural products for drug discovery
Biological targets: CNS, antiviral, antibacterial, antitumor and immunosuppressant
Natural products for drug discovery selection criteria • Unique chemical scaffold • Easily accessible • Continuous large scale re-supply • Can be obtained by total synthesis/ semi-synthesis
N
H3CO O OCH3
thebaine
N
H3CO
H3CO
OCH3
H3CO
CH3H
(S)-laudanosine
NCH3
HO
H3CO
OHH3CO
H
boldineHO
H
OOH
betulinic acid
example of NP scaffolds
Why natural products?
4
All new approved drugs 1981-2010
David J. Newman and Gordon M. Cragg, J. Nat. Prod. 2012, 75, 311-335
“B” Biological; large peptides or proteins. “S” Totally synthetic drug, often found by random screening. “S*” Made by total synthesis, but the pharmacophore is/was from a natural product. “V” Vaccine.
“N” Natural product. “ND” Derived from a natural product. “NM” Natural product mimic. Total = 626
Total number =1355
Why natural products?
5
NPs occupy a unique chemical space in biological system Structurally considered “privileged” which contain functional elements likely to
confer biological activity, “drug-like” properties Obey Lipinsky’s “rule of five”
60 % 126,140 of NPs from The Dictionary of NPs had no violations 85% of 814 NPs had no violations1
Challenges working with NPs Isolation and Structure Elucidation
Limitation of NPs for compound development/biological development Continual resupply of large amounts of NPs Resource sustainability
1. Ronald J. Quinn et al. J. Nat. Prod. 2008, 71, 464 2. M. Feher et al. J. Chem. Inf. Comp. Sci. 2003, 43, 218
Alkaloid-like chemical scaffolds cyclic imines
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NH
HN
H
H
O
NH
NH
O
aristotelinone makonine
NH
HN
H
H
aristoteline
Aristotelia-type alkaloids, containing aza
bicyclo [3
.3.1] system
Aristotelia chilensisAristotelia
austaliasica
N
O
Me
O
H
H
O
Me
O
MeO H
11(Z)-1',2'-didehydrostemofoline
HN
OOOHN
H
N
COOCH3
Coronaridine
Tabernaemontana australisgalanthamine
Galanthus spp.
Alkaloids contain the common
benzazepine core cyclic structure
Stemona sp.
HN NHCOCH3HH
H
CH3H
1
N
HN
O
R1
86
9 51
R1
2
Current Research Optically active cyclic imines
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Alkaloid-like compounds having fused ring chemical scaffolds can be obtained in one single step from inexpensive starting materials.
Steve Williams PhD student
Matthew Phillips PhD student
N
HN
O
R
86
95 1
RCN,
5
H2SO4
R
(1S,5S,6S)
4
77%
[α]D = +106
(c
1.18, CH2Cl2)
(-)-β-pinene
N
NHR
O
RCN,
H2SO4
(R)-(+)
-limonene6
R
(1R,5R,6R)
61%
[α]D = -104
(c 1.24, CH2Cl2)
H2C
CH2
N R
NHO
R
i. H2SO4
,RCN
ii. H2O
34 XiXi Xu
PhD student
Alkaloid-like chemical scaffolds Biological Screening
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AChE inhibitory Anticancer
In collaboration with Dr Tristan Rawling (MAPS, UTS) In collaboration with A/Prof Mary Bebawy (Graduate School of Health, UTS)
Lilly OIDD broad biological screening Therapeutic areas
Diabetes, cardiovascular, immunology, neurodegeneration and pains and oncology
Neglected and Tropical diseases Malaria and tuberculosis
Biological activities so far: Anticancer AChE inhibitors Antimalaria (Plasmodium falciparum)
Drug Discovery from Thai herbal medicines Stemona spp Our collaborators: Chiang Mai University and UOW
New biological activities AChE inhibitors Reverse MDR in cancer cells via the inhibition of P-gp function
Commercial outcome Formulation of plant crude extracts as biopesticide
Roots of Stemona tuberosa for sale in Chiang Mai Thailand
N
OMe
HMe
OMeMe
O
OO
(11Z)- 1',2'-didehydrostemofoline
Traditional uses of plant extracts Biological activities of individual alkaloids and derivatives
Bronchitis Anthelminthic Tuberculosis Anti-tussive
Anthelminthic Anti-feedant Anti-tussive AChE inhibitor
herbal pesticide Reverse MDR in cancer cells
Umsumarng, S; Pitchakarn, P; Sastraruji, K; Yodkeeree, S; Ung, A.T.; Pyne, S. G.; Limtrakul, P. Basic & Clinical Pharmacology & Toxicology (2015), 116(5), 390. - Sastraruji, K; Sastraruji, T; Ung, A.T.; Griffith, R; Jatisatienr, A; Pyne, S. G. Tetrahedron (2012), 68(35), 7103-7115
Drug discovery from traditional herbal medicines Our collaborators Traditional Chinese Medicine (TCM, SoLS, UTS) Chulalongkorn University, Thailand
Therapeutic areas Pains and neurodegenerative diseases
Approaches Identifying phytochemical components Broad biological screening of isolated compounds Human clinical trails (TCM, SoLS, UTS)
Research outcomes would enable us to Identify new indications for the herbs Improve formulation and potency of the whole herbs Identify new chemical space for drug discovery
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Natural product inspired FtsZ inhibitors In collaboration with Prof Liz Harry (I3) FtsZ inhibitors as novel antibiotics Bactericidal compounds have been discovered
N S
O
F
F
NH2
O
Cl
FtsZ inhibitor
antibaterial agent
PC190723
Matthew Payne PhD student
Matthew Phillips PhD student
• Ken Kusuma PhD student • Helena Dorothy Honours student
FtsZ protein
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Dr Tristan Rawling Novel lipid-derived anticancer agents
• Omega-3 fatty acids like EPA have anticancer properties. We identified a metabolite of EPA that inhibits cell growth (ω-3-epoxy-EPA), and have adapted it into a new class of anticancer agents that reduce the growth and metastasis of breast cancer.
Reduces MDA-MB-231 breast cancer cell growth
Control
ω-3-EEA (10 μM)
Tum
our
wei
ght (
g)
Reduces primary tumour growth in vivo
O
OH
eicosapentaenoic acid (EPA)
O
OH
Oω-3-epoxy-EPA (lead compound)
CYP
OOH
O
N N
O
O
OHH H
N N
O
O
OHH H
N N
O
O
OHH H
Cl
F
FF
SAR
antimetastatic Cell killing (apoptosis)Prevents formation of secondary tumours in vivo Tumour foci
control treated
Contact details
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A/Prof. Alison Ung Email: [email protected] http://www.uts.edu.au/staff/alison.ung Area of expertise: Drug design and synthesis, Natural product drug discovery, Natural products Chemistry, Organic Synthesis and Computer-aided drug design. Central contact: Prof. Bradley Williams Position: Associate Head of School (Strategic Development) Email: [email protected]
