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

摘要

The following document contains the results of Ph.D. thesis research that was focused toward the isolation and complete structural characterization of new molecules that were effective in the treatment and prevention of cancer. The use of marine sediment-derived actinomycetes as a novel source for the chemical entities led to the isolation of three distinct suites of molecules with unprecedented carbon skeletons each of which displayed some anticancer properties.; In the first project, three potent 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.i 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 potent 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).ii The planar structures, elucidated via spectroscopic and chemical methods, consisted of 26-membered polyunsaturated macrolactones containing repeating vicinal hydroxyl methoxyl moieties. The relative and absolute 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. At present, the anticancer properties of the arenicolides are being evaluated in several cancer chemoprevention and anticancer enzyme target based assays. 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 isolation and characterization of a novel class of molecules that are likely polyketide derived and exhibit inhibitory activity against the enzyme aromatase. These molecules, the pyridinopyrones, were isolated from a marine sediment-derived Streptomyces sp and their chemical structures were solved by various spectral methods. The relatively simple chemical structure of the pyridinopyrones makes these molecules attractive targets for synthetic modification and structure activity relationship studies directed toward improving their inherent aromatase inhibitory activity.