FUNCTIONAL ANALYSIS AND MODIFICATION OF NOVEL MACROLACTAM ANTITUMOR ANTIBIOTIC

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A novel 20-membered macrolactam glycoside antibiotic was studied based on its interesting chemotherapeutic activity against human solid tumors. To get some insight into the molecular basis of its function, search for related products, total synthesis, chemical modification, simplification and biosynthetic studies were carried out. A total synthesis was completed by developing a new synthetic method of vicenisamine and related aminosugars from non-carbohydrate starting materials and by constructing the macrolactam aglycon from (S)-citronellol by using Suzuki-cross coupling and asymmetric aldol reactions as key step. The fermentation of the producing organism Streptomyces sp. HC-34 was further screened and a new analog, named as vicenistatin M having a neutral sugar D-mycarose instead of vicenisamine aminosugar, was isolated. A key finding with vicenistatin M was that an aminosugar is essential for the antitumor activities. The structure was ultimately determined by its total synthesis. … More Chemically synthesized kedarosamine, a key aminosugar of antibiotic kedarcidin Chromophore, was transglycosylated to the vicenistatin aglycon and the resulting 4'-epi-vicenistatin and 4'-epi-α-vicenistatin was found to have slightly reduced cytotoxic activity. Important observation in the structural simplification studies was that 3,7-dimethyloctyl β-vicenisaminide showed a comparable intense cytotoxicity to vicenistatin. Methylation of the amide nitrogen of the aglycon induced conformational flipping of the vicenistatin aglycon, the cytotoxicity of which was reduced to 1/40. Apparently. the conformation of the aglycon plays a significant role for the activity. Fluorescence labeling was also attempted by introducing a pyrenyl function into visenisamine or the amide function. To improve the solubility of vienistatin, a lactone aglycon rather than a lactam was totally synthesized and further elaboration to vicenisaminide aglycon has been continued. The biosyrthesis pathway of vicenistatin was elucidated by isotope-tracer technology. A key feature is the formation of the starter unit of the polyketide aglycon that involves a stereospecific molecular rearrangement of glutamic acid into 3-methylaspartic acid. Less