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Title: Total synthesis of antibiotic varacins B and C, design and synthesis of the core functionalities of leinamycin and investigation of their biological properties
Authors: Lee, Ho-fai
Degree: Ph.D.
Issue Date: 2003
Abstract: Part I. Synthesis of Leinanlycin'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. In the first place of our research, we have attained the synthesis of two Molecules 1 and 2, the core functionalities of leinamycin, via a 15-plus synthetic operations pathway. The detailed synthesis of leinamycin's cores, 1 and 2, as well as their biological properties will be presented in the text accordingly. Secondly, we have attempted to employ our cores to mimic leinamycin and study their DNA-cleaving mechanisms. It is the first time the existence of hard evidence that has been proven beyond reasonable doubt 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. In such a way, the mimics are not only brought closely to target DNA but also confined to a specific region within the duplex. This part of our study has paved the road for the future works of further evaluation of the leinamycin's DNA-cleaving mechanisms and exploration of modified antibiotic for the candidates of anticancer drugs. 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. Moreover, conduction of the total synthesis of varacins B and C as well as the designe and synthesis of their structural analogs have not yet been reported in literature. With the aim of clarifying the mode of actions, a set of structural analogs of varacins B and C were designed and synthesized. Furthermore, we demonstrated for the first time that these synthetic analogs could cleave DNA efficiently under physiological condition. Based upon the encouraging results, the research focuses were turned on the total syntheses of varacins B and C, the designs and synthesis of structural derivatives of the family of varacin. 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. It is believed that our endeavors of this project is not only providing chemists with a new insight into the chemistry that has been long utilized in nature, but also ultimately lay a theoretical foundation for the scientific contributions in the field of cancer chemotherapy and integrity in the study of varacin's family. Part III. Varacins B, C and Benzotrithiole Oxides Structural Analogs as A Novel Family of Photoinducible DNA Cleaving- Agents The design and synthesis of DNA cleaving agents are of great interest as a workhorse in chemistry, biology and medicine. During our elaborated research on the antibiotics varacin B, varacin C and the structural related moieties as the thiol-mediated DNA-cleaving candidates, 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. Meanwhile, intersystem crossing D* + A->D + A* (one of the quenching mechanism) then generated the hydroxyl radical in aqueous medium and cleaved the DNA strands in the system. This field of study constitutes a timely and challenging topic and leads to the development of pageantic applications including DNA footprinting techniques and anticancer research.
Subjects: Hong Kong Polytechnic University -- Dissertations
Antineoplastic agents
Pages: v, 446 leaves : ill. ; 30 cm
Appears in Collections:Thesis

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