A/Prof Alison Ung Natural products-led drug discovery UTS:SCIENCE science.uts.edu.au UTS CRICOS PROVIDER CODE: 00099F
Who we Are Team AMaM A dvanced M olecules and M aterials Multidisciplinary Tristan Rawling team of Chemists, Physicists and Materials Scientists science.uts.edu.au
Drug Discovery from Natural Product Derived Scaffolds 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 • H 3 CO N HO N H 3 CO CH 3 H N H H 3 CO CH 3 H O O OCH 3 H 3 CO OH H 3 CO boldine thebaine H 3 CO OCH 3 HO -laudanosine betulinic acid OH (S) example of NP scaffolds science.uts.edu.au
Why natural products? All new approved drugs 1981-2010 “N” Natural product. “ND” Derived from a natural product. “NM” Natural product mimic. Total = 626 Total number =1355 “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. David J. Newman and Gordon M. Cragg, J. Nat. Prod. 2012 , 75, 311-335 4
Why natural products? 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 violations 1 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 5
Alkaloid-like chemical scaffolds cyclic imines Alkaloids contain the common benzazepine core cyclic structure H CH 3 H N N H NHCOCH 3 HN MeO Me H H H Me N N O OH H COOCH 3 H O O O O O H 1 Coronaridine galanthamine -1',2'-didehydrostemofoline 11( Z ) Tabernaemontana australis Galanthus spp. Stemona sp. Aristotelia-type alkaloids, containing aza bicyclo system [3.3.1] Aristotelia austaliasica Aristotelia chilensis R 1 N O O H H 1 9 H 5 H N 8 N N H 6 H H N HN R 1 N N H H H 2 O aristoteline makonine aristotelinone science.uts.edu.au
Current Research Optically active cyclic imines Alkaloid-like compounds having fused ring chemical scaffolds can be obtained in one single step from inexpensive starting materials. H 2 C N R i. H 2 SO 4 ,RCN ii. H 2 O CH 2 R NH 3 4 O XiXi Xu PhD student N R RCN, 4 N R RCN, 5 9 1 H 2 SO 4 H 2 SO 4 6 77% 8 NH R 61% HN R - - β -pinene ( ) 6 O 5 - -limonene O (+) ( R ) Steve Williams (1 R ,5 R ,6 R ) (1 S ,5 S ,6 S ) PhD student Matthew Phillips = +106 (c 1.18, CH 2 Cl 2 ) = -104 (c 1.24, CH 2 Cl 2 ) [ α ] D [ α ] D PhD student science.uts.edu.au
Alkaloid-like chemical scaffolds Biological Screening 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 ) science.uts.edu.au
Drug Discovery from Thai herbal medicines Stemona spp Our collaborators: Chiang Mai University and UOW Traditional uses of plant extracts Biological activities of individual alkaloids and derivatives Bronchitis Anthelminthic Tuberculosis Anti-tussive Roots of Stemona tuberosa Anthelminthic Anti-feedant for sale in Chiang Mai Thailand Anti-tussive AChE inhibitor Me OMe Me herbal pesticide Reverse MDR in cancer cells O H O N O Me New biological activities O - 1',2'-didehydrostemofoline (11 Z ) AChE inhibitors Reverse MDR in cancer cells via the inhibition of P-gp function Commercial outcome Formulation of plant crude extracts as biopesticide 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 science.uts.edu.au
Natural product inspired FtsZ inhibitors In collaboration with Prof Liz Harry (I3) FtsZ inhibitors as novel antibiotics Bactericidal compounds have been discovered Matthew Payne PhD student Cl • Ken Kusuma PhD student • Helena Dorothy S N Honours student O F O NH 2 F FtsZ inhibitor antibaterial agent PC190723 Matthew Phillips FtsZ protein PhD student
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. H O Reduces MDA-MB-231 eicosapentaenoic acid (EPA) O breast cancer cell growth CYP H O O O ω -3-epoxy-EPA (lead compound) Control H O O O O ω -3-EEA (10 μ M) H H N N H O O Reduces primary tumour SAR growth in vivo O H H O F H H F N N N N H O Tumour weight (g) H O F O Prevents formation of antimetastatic Cell killing (apoptosis) O Cl secondary tumours in vivo Tumour foci control treated science.uts.edu.au
Contact details A/Prof. Alison Ung Email: Alison.Ung@uts.edu.au 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: Bradley.Williams@uts.edu.au science.uts.edu.au
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