Our long-term objective is to discover and develop leads for new anticancer agents. This research utilizes a collaboration between the Marine Bioorganic Chemistry group at U. of California Santa Cruz (UCSC) led by Prof. P. Crews and the Developmental Therapeutics Program at the Josephine Ford Cancer Center (JFCC) led by Dr. F. A. Valeriote. The hypothesis is that small molecule natural products (<2000 amu), can be identified and used, to selectively inhibit the growth of solid cancer tumors.
The aims outlined below will provide a foundation to discover and explore new biomolecules that will be of broad interest while also addressing general hypotheses guiding this research. Our focus is on tumors with relative insensitivity to most of the standard anticancer drugs. Thus, the overall aim is to obtain new compounds with effective activity against solid tumors, especially pancreatic, colo-rectal, breast, prostrate, brain, ovarian, and lung cancers. The general aims for the next grant period are: 1. To mine our repository of unstudied sponges either to continue or to begin new studies on both known and new bioactive, small biomolecules. 2. To use marine-derived fungi cultured in various media as a source for new active small biomolecules. 3. To use and refine our sponge-inspired hypothesis as the rationale for pursuing culture of Gram-positive and Gram-negative bacteria as a source of new active small biomolecules. 4. To utilize the in vitro cytotoxicity disk diffusion assay network to identify extracts obtained from Aims 1, 2, and 3 with solid tumor selectivity for follow-up fractionation and SAR expansion in Aim 6. 5. To make use of promising analytical methodologies, especially DART MS and DANS NMR, to guide further work on marine extracts, fractions, and library pure compounds obtained from Aims 1, 2, and 3. 6. To efficiently isolate, characterize and/or dereplicate compounds by focusing on the priority hits identified in Aims 4 and 5. 7. To continue capstone studies of solid tumor selective compounds through pharmacology evaluations and therapeutic assessment.
The aim of this application is to discover and develop leads for new anticancer agents with a focus on tumors with relative insensitivity to most of the known anticancer drugs. The overall aim is to obtain new compounds from sponges and associated microorganisms with effective activity against solid tumors, especially pancreatic, colo-rectal, breast, prostrate, brain, ovarian, and lung cancers. This research utilizes a long-term collaboration between the Marine Bioorganic Chemistry group at U. of California Santa Cruz (UCSC) led by Prof. P. Crews and the Developmental Therapeutics Program at the Henry Ford Cancer Center (HFCC) led by Dr. F. Valeriote.
|Lorig-Roach, Nicholas; Hamkins-Indik, Frances; Johnson, Tyler A et al. (2018) The potential of achiral sponge-derived and synthetic bromoindoles as selective cytotoxins against PANC-1 tumor cells. Tetrahedron 74:217-223|
|Cooper, Jason K; Li, Kelin; Aubé, Jeffrey et al. (2018) Application of the DP4 Probability Method to Flexible Cyclic Peptides with Multiple Independent Stereocenters: The True Structure of Cyclocinamide A. Org Lett 20:4314-4317|
|Fraley, Amy E; Garcia-Borràs, 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|
|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|
|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:|
|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|
|Lorig-Roach, Nicholas; Still, Patrick C; Coppage, David et al. (2017) Evaluating Nitrogen-Containing Biosynthetic Products Produced by Saltwater Culturing of Several California Littoral Zone Gram-Negative Bacteria. J Nat Prod 80:2304-2310|
|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|
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