Natural products-led drug discovery UTS:SCIENCE science.uts.edu.au - - PowerPoint PPT Presentation

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Natural products-led drug discovery UTS:SCIENCE science.uts.edu.au - - PowerPoint PPT Presentation

Jul 08, 2023 103 likes •257 views

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,

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UTS:SCIENCE

UTS CRICOS PROVIDER CODE: 00099F

A/Prof Alison Ung

Natural products-led drug discovery

science.uts.edu.au

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science.uts.edu.au

Who we Are

 Team AMaM  Advanced

Molecules and Materials

 Multidisciplinary

team of Chemists, Physicists and Materials Scientists

Tristan Rawling

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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 CH3 H (S)

  • laudanosine

N CH3 HO H3CO OH H3CO H boldine HO H O OH betulinic acid

example of NP scaffolds

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Why natural products?

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 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

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Why natural products?

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 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
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Alkaloid-like chemical scaffolds cyclic imines

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N H H N H H O N H N H O aristotelinone makonine N H H N H H aristoteline

Aristotelia-type alkaloids, containing aza bicyclo [3.3.1] system

Aristotelia chilensis Aristotelia austaliasica

N O Me O H H O Me O MeO H

11(Z)

  • 1',2'-didehydrostemofoline

H N O O OH N H N COOCH3

Coronaridine Tabernaemontana australis galanthamine Galanthus spp.

Alkaloids contain the common benzazepine core cyclic structure

Stemona sp.

HN NHCOCH3 H H H CH3 H

1

N HN O R1

8 6 9 5 1

R1 2

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Current Research Optically active cyclic imines

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 Alkaloid-like compounds having fused ring chemical scaffolds can be

  • btained in one single step from inexpensive starting materials.

Steve Williams PhD student Matthew Phillips PhD student

N HN O R

8 6 9 5 1

RCN, 5 H2SO4 R (1S,5S,6S) 4 77% [α]D = +106 (c 1.18, CH2Cl2) (

  • )
  • β-pinene

N NH R O RCN, H2SO4 (R)

  • (+)
  • limonene

6 R (1R,5R,6R) 61% [α]D = -104 (c 1.24, CH2Cl2) H2C CH2 N R NH O R

  • i. H2SO4,RCN
  • ii. H2O

3 4 XiXi Xu PhD student

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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

  • ncology

 Neglected and Tropical diseases  Malaria and tuberculosis  Biological activities so far:  Anticancer  AChE inhibitors  Antimalaria (Plasmodium falciparum)

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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 O Me H Me OMe Me O O O (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
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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

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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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science.uts.edu.au

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)

Tumour weight (g)

Reduces primary tumour growth in vivo

O O H eicosapentaenoic acid (EPA) O O H O ω-3-epoxy-EPA (lead compound) CYP O O H O N N O O O H H H

N N O O O H H H N N O O O H H H Cl

F F F

SAR

antimetastatic Cell killing (apoptosis)

Prevents formation of secondary tumours in vivo Tumour foci control treated

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Contact details

science.uts.edu.au

 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