TOTAL SYNTHESEIS OF BIOXALOMYCIN, ET743 AND TETRAZOMINE

描述：(主要调查人员摘要)这项工作的具体目标 项目是研究抗肿瘤抗生素的相互作用，包括 喹诺卡星、四唑胺、双恶霉素类和环孢菌素743与细胞 核酸。这些药物的DNA烷基化能力与它们的 本课程将探讨对核酸造成氧化损伤的能力。这个 合成这类抗肿瘤药物的成员将继续 开发的目标是利用开发的综合方法论 制造毒性更低、选择性更强、药效更强的新的抗肿瘤药物。在……里面 此外，还将利用综合工具来综合机械手 这些物质与细胞核酸相互作用的探针和 与细胞核酸结合的蛋白质。 我们最近发现，比奥沙霉素α2特异地与 5‘cg3’步的双链DNA。我们建议阐明确切的分子 共价加合物的结构。这一发现启发了新的设计理念 对于基于奎诺卡星/比奥沙霉素/ET743核心的更简单的类似物，可以 能够使DNA发生交叉连接。加上这些研究，我们建议 检测比奥沙霉素等对DNA与DNA结合蛋白的交联作用 743和几个人工合成的杂交体；感兴趣的蛋白质是High 迁移率组(HMG)与DNA相关的非组蛋白染色体蛋白 小凹槽。

DESCRIPTION: (Principal Investigator's Abstract) The specific aims of this program are to study the interaction of the antitumor antibiotics, including quinocarcin, tetrazomine, the bioxalomycins and ecteinascidin 743 with cellular nucleic acids. The DNA-alkylating capacity of these drugs compared with their ability to cause oxidative damage to nucleic acids will be explored. The synthesis of members of this class of antitumor drugs will continue to be developed with the objective of harnessing the synthetic methodology developed to make new, less toxic, more selective and more potent antitumor drugs. In addition, the tools of synthesis will be exploited to synthesize mechanistic probes for the interaction of these substances with cellular nucleic acids and proteins that bind to cellular nucleic acids. We have recently discovered that bioxalomycin alpha2 specifically cross-links duplex DNA at 5'CG3' steps. We propose to elucidate the exact molecular structure of the covalent adduct. This finding has inspired new design concepts for simpler analogs based on the quinocarcin/bioxalomycin/Et 743 core that may be capable of cross-linking DNA. Coupled to these studies, we propose to examine the cross-linking of DNA to DNA-binding proteins by bioxalomycin, Et 743 and several synthetic hybrids; the proteins of interest are the High Mobility Group (HMG) nonhistone chromosomal proteins that associate with DNA in the minor groove.