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Marine sediment-derived actinomycetes : prolific sources of new molecules with the potential for the treatment and prevention of cancer

  • Author(s): Miller, Eric David
  • et al.
Abstract

The following document contains the results of Ph.D. thesis research that was focused toward the complete structural characterization of molecules that were effective in the treatment and prevention of cancer. The use of marine sediment-derived actinomycetes as a source for the chemical entities led to the isolation of three suites of molecules with unprecedented carbon skeletons each of which displayed some anticancer properties. In the first project, three cancer cell cytotoxins, piperazimycins A-C (1-3), were isolated from the fermentation broth of a Streptomyces sp., cultivated from marine sediments near the island of Guam.¹ The structures of these cyclic hexadepsipeptides were assigned by a combination of spectral, chemical and crystallographic methods. The piperazimycins were found to be composed of rare amino acids, including hydroxy-acetic acid, [alpha]- methyl-serine, [gamma]-hydroxypiperazic acid and [gamma]- chloropiperazic acid. The novel amino acid residues 2- amino-8-methyl-4,6-nonadienoic acid and 2-amino-8-methyl-4, 6-decadienoic acid were found as components of piperazimycins A and C, respectively. When screened in the National Cancer Institute's 60 cancer cell line panel, piperazimycin A exhibited in vitro cytotoxicity toward multiple tumor cell lines with a mean GI₅₀ of 100 nM. In the second project, chemical evaluation of the saline fermentation broth of several strains of the obligate marine actinomycete Salinispora arenicola led to the identification of three new macrolide polyketides designated arenicolides A-C (1-3). The planar structures, elucidated via spectroscopic and chemical methods, consisted of 26-membered polyunsaturated macrolactones containing repeating vicinal hydroxyl methoxyl moieties. The stereochemistries of 1-3 were assigned by a combination of J-based configurational analyses and chemical derivatization. The arenicolides displayed moderate cytotoxicity in an in vitro colon adenocarcinoma cell-line (HCT-116) assay and also in the National Cancer Institute's 3 cancer cell line panel. Due to their structural novelty, the NCI has also recently agreed to reevaluate the cytotoxic activity of the arenicolides in the 60 cancer cell line panel. The final chapter is focused on the characterization of a novel class of likely polyketide derived molecules that exhibit inhibitory activity against the enzyme aromatase. These potent aromatase inhibitors, the pyridinopyrones, were isolated from a marine sediment-derived Streptomyces sp and their chemical structures were solved by various spectral methods

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