Board of Trustees Meeting - UNC Greensboro...Board of Trustees Meeting . The University of North...
Transcript of Board of Trustees Meeting - UNC Greensboro...Board of Trustees Meeting . The University of North...
-
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