TOTAL SYNTHESEIS OF BIOXALOMYCIN, ET743 AND TETRAZOMINE

描述：（主要研究者摘要）本研究的具体目的 研究抗肿瘤抗生素的相互作用，包括 奎奴卡星、四唑明、双孢霉素和海鞘素743与细胞 核酸这些药物的DNA烷基化能力与其 将探索引起核酸氧化损伤的能力。的 这类抗肿瘤药物的合成将继续是 目的是利用所开发的综合方法， 来制造新的、毒性更小的、更有选择性的和更有效的抗肿瘤药物。在 此外，还将利用综合工具，综合机理 用于这些物质与细胞核酸相互作用的探针， 与细胞核酸结合的蛋白质。 我们最近发现，双曲霉素α 2特异性地交联 双链体DNA的5 'CG 3'步骤。我们建议阐明 共价加合物的结构。这一发现激发了新的设计理念 对于基于奎奴卡星/双霉素/Et 743核心的更简单的类似物， 能够交联DNA。结合这些研究，我们建议 研究了双霉素（Bioclonomycin，Et）对DNA与DNA结合蛋白的交联作用 743和几个合成杂交体;感兴趣的蛋白质是高蛋白质。 迁移率组（HMG）非组蛋白染色体蛋白，与DNA相关， 小沟

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.