Board of Trustees Meeting The University of North Carolina at Greensboro

Day Hikes for New Medicines September 5, 2014

Nicholas H. Oberlies, Ph.D. Associate Professor

Chemistry & Biochemistry

September 5, 2014 Slide 1

Goals of the Presentation

• History of natural products drug discovery

• Why study fungi

• How do we search for new drug leads

• Example research project

September 5, 2014 Slide 2

Goals of the Presentation

September 5, 2014 Slide 3

Drugs Derived from Natural Products

Newman & Cragg, J. Nat. Prod. 2012, 75, 311-335

All new approved drugs, 01/1981-2010, by source (N = 1355)

All anticancer drugs, 1940s-2010, by source (N = 175)

S, 387, 29%

ND, 299, 22%

NB, 5, 0% N, 59, 4%

B, 202, 15%

V, 80, 6%

S*/NM, 122, 9%

S*, 55, 4% S/NM, 146,

11% S, 44, 21%

ND, 57, 28% NB, 1, 0% N, 27, 13%

B, 26, 13%

V, 5, 2%

S*/NM, 8, 4%

S*, 20, 10

S/NM, 18, 9%

B: Biological N: Natural product NB: Natural product “Botanical” ND: Derived from a natural product

S: Totally synthetic S*: Made by total synthesis, but the pharmacophore is/was from a natural product V: Vaccine NM: Natural product mimic

September 5, 2014 Slide 4

Taxol and Camptothecin from RTI

Oberlies & Kroll, J. Nat. Prod. 2004, 67, 129-135

September 5, 2014 Slide 5

Penicillins Penicillium

Cephalosporins Acremonium

Griseofulvin Penicillium griseofulvum

Cyclosporin A Tolypocladium inflatum

Lovastatin Aspergillus terreus

Fingolimod Isaria sinclairii

Historically Important Fungal Metabolites

September 5, 2014 Slide 6

Fungi are Vastly Under Studied

Hawksworth, D.L. (1991) Mycol. Res. 95, 641-655; Blackwell, M. (2011) Am. J. Bot. 98, 426-438

Bioactivity-directed Fractionation

Prioritization Screening

Medicinal Chemistry (camptothecin)

Supply Issues (taxol)

Source

Extract

Bioassay

Bioassay

Fractionate

Purify

Structure Elucidation

Lead

Mechanism of Action

Drug Slide 7

September 5, 2014 Slide 8

Diverse Fungal Libraries

September 5, 2014 Slide 9

New Biodiversity, New Chemistry, New Ph.D.

El-Elimat et al. (2014) J. Nat. Prod. 77, in press

September 5, 2014 Slide 10

New Biodiversity

September 5, 2014 Slide 11

New Chemistry, New Drug Leads Table 6. Activities of Compounds 1‒7, 9-11, and 13-14 Against Two Human Tumor Cell Lines

compounda IC50 values in µMb

MDA‒MB‒435c HT‒29c 1 14.1 >20 4 14.1 >20 5 2.9 7.5 6 14.5 13.8 10 11.2 25.4 aCompounds 2, 3, 7, 9, 11, 13, 14 were inactive (IC50 values >20 µM). bIC50 values were determined as the concentration required to inhibit growth to 50% of control with a 72 h incubation. cPositive control was vinblastine tested at concentration of 1 nM in MDA‒MB‒435 cells and 10 nM in HT‒29 cells, which had 21% and 44% viable cells, respectively.

1

3

5

79

1113

15 1718

19

O

OO

HO

O

September 5, 2014 Slide 12

Spectacular Investment in Research

El-Elimat et al. (2013) J. Nat. Prod. 76: 1709-1716

September 5, 2014 Slide 13

Funded Research Collaborations

Biotechnology Research Grant (2011-BRG-1206) Collaborative Funding Grant (2011-CFG-8008)

September 5, 2014 Slide 14

UNCG does Cutting Edge Chemistry Research

Slide Number 1Goals of the PresentationGoals of the PresentationDrugs Derived from Natural ProductsTaxol and Camptothecin from RTIHistorically Important Fungal MetabolitesFungi are Vastly Under StudiedSlide Number 8Diverse Fungal LibrariesNew Biodiversity, New Chemistry, New Ph.D.New BiodiversityNew Chemistry, New Drug LeadsSpectacular Investment in ResearchFunded Research CollaborationsUNCG does Cutting Edge Chemistry Research