The proposed research involves development of a concise, novel, biomimetic route for a synthesis of the communesins, a class of molecules exhibiting strong biological activity against a number of tumor cell lines. The chemistry investigated essentially consists of three parts: 1) discovery and development of a methodology for stereoselective radical/enolate coupling, 2) use of this methodology and known chemistry to access complex intermediates, which 3) will be used to elucidate the biosynthesis of the communesins. It is anticipated that the new methodology developed in parts 1) and 3) will facilitate the construction of analogues of the communesins and lead to a more profound understanding of the exhibited biological activity. Additionally, the chemistry developed will be broadly applicable and provide new disconnections and more facile access to compounds of clinical and medicinal importance.

Public Health Relevance

The proposed work aims at synthesis of compounds known to be toxic to a number of cancer cell lines. Chemistry developed in pursuit of the compounds is anticipated to allow efficient access to other targets of medicinal interest. ? ? ?

National Institute of Health (NIH)
National Cancer Institute (NCI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04A-T (20))
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Myrick, Dorkina C
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Colorado State University-Fort Collins
Schools of Arts and Sciences
Fort Collins
United States
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Guerra-Bubb, Jennifer M; Bowers, Albert A; Smith, William B et al. (2013) Synthesis and HDAC inhibitory activity of isosteric thiazoline-oxazole largazole analogs. Bioorg Med Chem Lett 23:6025-8
Bowers, Albert A; Walsh, Christopher T; Acker, Michael G (2010) Genetic interception and structural characterization of thiopeptide cyclization precursors from Bacillus cereus. J Am Chem Soc 132:12182-4
Bowers, Albert A; Acker, Michael G; Koglin, Alexander et al. (2010) Manipulation of thiocillin variants by prepeptide gene replacement: structure, conformation, and activity of heterocycle substitution mutants. J Am Chem Soc 132:7519-27
Walsh, Christopher T; Acker, Michael G; Bowers, Albert A (2010) Thiazolyl peptide antibiotic biosynthesis: a cascade of post-translational modifications on ribosomal nascent proteins. J Biol Chem 285:27525-31
Acker, Michael G; Bowers, Albert A; Walsh, Christopher T (2009) Generation of thiocillin variants by prepeptide gene replacement and in vivo processing by Bacillus cereus. J Am Chem Soc 131:17563-5
Bowers, Albert A; West, Nathan; Newkirk, Tenaya L et al. (2009) Synthesis and histone deacetylase inhibitory activity of largazole analogs: alteration of the zinc-binding domain and macrocyclic scaffold. Org Lett 11:1301-4
Bowers, Albert A; Greshock, Thomas J; West, Nathan et al. (2009) Synthesis and conformation-activity relationships of the peptide isosteres of FK228 and largazole. J Am Chem Soc 131:2900-5