Total synthesis of antibiotic varacins B and C, design and synthesis of the core functionalities of leinamycin and investigation of their biological properties

Part I. Synthesis of leinamycin's core functionalities as anti-cancer drug candidates and study of their thiol-activated DNA-cleaving activities. Leinamycin, discovered in 1989, is the only antibiotic ever found in nature possessing 1,2-dithiolan-3-one 1-oxide moiety which embedding a spiro fashion to an 18-membered lactam. This natural product displays potent antitumor activities and has been examined clinically as an anticancer drug candidate. It is the first time the existence of hard evidence has been proven if 1,2-dithiolan-3-one 1-oxide functionality existed alone, the thiol-mediated DNA-cleavage was through a radical mechanism, if there is 1,2-dithiolan-3-one 1-oxide and C6-C7 olefinic double bond co-existed in the molecule, both the alkylation and radical mechanisms prevailed. In addition, we have engaged our two molecules to the linkers. This is an approach headed for linking our mimics covalently to antisense oligonucleotides.; Part II. Exploring the antibiotics varacin, varacin B, varacin C and the structural related entities for anti-cancer drug candidates. Varacins B and C, isolated from the Far Eastern ascidian Polycitor sp. in 1995, are the first antibiotics discovered to date that having the unique structural feature of trithiole 1-oxide as their core functionality. Although biological examinations on these two natural products revealed that both of them exhibit potent antifungal and antimicrobail activities against Candida albicans and Bacillus subtilus, the modes of their actions at the molecular level have not yet been understood. With the aim of clarifying the mode of actions, a set of structural analogs of varacins B and C were designed and synthesized. The objectives of our works are to characterize the precise DNA-cleaving mechanisms of varacins B and C and to evaluate the suitability of those title compounds, the structural related derivatives as the candidates of anticancer drugs or lead drugs.; Part III. Varacins B, C and benzotrithiole oxides structural analogs as a novel family of photoinducible DNA cleaving-agents. We have accidentally uncovered the photoinduced DNA-cleaving properties of the benzotrithiole oxide, and varacin B, varacin C which incorporated benzotrithiole oxide entity in the molecules. Based on the preliminary results from the mechanical studies and DNA cleavage assays, we proposed the photochemical cleavage of DNA by the candidates was originated from the photolysis of benzotrithiole oxide to yield a singlet excited state, which was rapidly transformed to the strained intermediate then backed to ground state with intramolecular oxygen migration. (Abstract shortened by UMI.)...