The aim of this renewal grant application is to continue the discovery of new marine natural products with activity against solid tumors, especially colo-rectal, breast, prostrate, brain, ovarian, and lung cancers. Our focus is on tumors with relative insensitivity to most of the known anticancer drugs. Attention is on the natural products from chemically rich organisms. This includes sponges, sponge-derived fungi, and sediment-derived fungi. The program continues the effective ongoing collaboration between the Natural Products group at U. of California Santa Cruz (UCSC) lead by Prof. Crews and the Experimental Therapeutics Program at the Henry Ford Cancer Center (HFCC) lead by Prof. Valeriote. This research will extend the evaluation of the natural products being discovered at UCSC through their testing in the cellular screens at HFCC and in a new yeast-based assay to be carried out at UCSC.
The aims for the next grant period are: 1. To use sponges as the source for new bioactive, small biomolecules employing the mammalian cell, yeast-based, or enzyme assays. 2. To use sponge-derived fungi as a source for new active, small biomolecules employing the mammalian cell, yeast-based, or enzyme assays. 3. To use sediment-derived fungi as a source for new active, small biomolecules employing the mammalian cell, yeast-based, or enzyme assays. 4. To use the unique cytotoxicity disk diffusion assay as a primary screen to identify extracts with solid tumor selectivity for fractionation. 5. To make use of a yeast halo assay that includes synthetic lethality profiling to guide further work on marine extracts, fractions and library pure compounds by targeting for methionine aminopeptidases (MetAPs). 6. To efficiently isolate and characterize compounds by bioassay guided isolation of the 2% per year active hits identified in our two screens. 7. To engage in pharmacology studies on as many as five compounds annually. Discovery of Novel Cytotoxic Natural Products from Marine Sponges and Fungi Phillip Crews, University of California, Santa Cruz The aim of this renewal grant application is to continue the discovery of new marine natural products with activity against solid tumors, especially colo-rectal, breast, prostrate, brain, ovarian, and lung cancers. Our focus is on tumors with relative insensitivity to most of the known anticancer drugs. Attention is on the natural products from chemically rich organisms. This includes sponges, sponge-derived fungi, and sediment-derived fungi. The program continues the effective ongoing collaboration between the Natural Products group at U. of California Santa Cruz (UCSC) lead by Prof. Crews and the Experimental Therapeutics Program at the Henry Ford Cancer Center (HFCC) lead by Prof. Valeriote.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047135-21
Application #
7759199
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Fu, Yali
Project Start
1989-04-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
21
Fiscal Year
2010
Total Cost
$474,174
Indirect Cost
Name
University of California Santa Cruz
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
125084723
City
Santa Cruz
State
CA
Country
United States
Zip Code
95064
Johnson, Tyler A; Milan-Lobo, Laura; Che, Tao et al. (2017) Identification of the First Marine-Derived Opioid Receptor ""Balanced"" Agonist with a Signaling Profile That Resembles the Endorphins. ACS Chem Neurosci 8:473-485
Sabry, Omar M M; Goeger, Douglas E; Valeriote, Frederick A et al. (2017) Cytotoxic halogenated monoterpenes from Plocamium cartilagineum. Nat Prod Res 31:261-267
Fraley, Amy E; Garcia-BorrĂ s, Marc; Tripathi, Ashootosh et al. (2017) Function and Structure of MalA/MalA', Iterative Halogenases for Late-Stage C-H Functionalization of Indole Alkaloids. J Am Chem Soc 139:12060-12068
Zhang, Huawei; Dong, Menglian; Chen, Jianwei et al. (2017) Bioactive Secondary Metabolites from the Marine Sponge Genus Agelas. Mar Drugs 15:
Zhang, Huawei; Crews, Phillip; Tenney, Karen et al. (2017) Cytotoxic Phyllactone Analogs from the Marine Sponge Phyllospongia papyrecea. Med Chem 13:295-300
Lin, Sheng; McCauley, Erin P; Lorig-Roach, Nicholas et al. (2017) Another Look at Pyrroloiminoquinone Alkaloids-Perspectives on Their Therapeutic Potential from Known Structures and Semisynthetic Analogues. Mar Drugs 15:
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Zhang, Huawei; Loveridge, Steven T; Tenney, Karen et al. (2016) A new 3-alkylpyridine alkaloid from the marine sponge Haliclona sp. and its cytotoxic activity. Nat Prod Res 30:1262-5
Zhai, Ming-Ming; Li, Jie; Jiang, Chun-Xiao et al. (2016) The Bioactive Secondary Metabolites from Talaromyces species. Nat Prod Bioprospect 6:1-24

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