Diazoparaquinone Natural Products Chemistry

重氮对醌天然产物化学

• 批准号: 0956458
• 负责人: Ken Feldman
• 金额: $ 45万
• 依托单位: Pennsylvania State Univ University Park
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0956458&HistoricalAwards=false
• 关键词: Diazoparaquinone; Natural; Products; Chemistry

Funding from the Chemical Synthesis Program of the Chemistry Division of the National Science Foundation will enable Dr. Ken Feldman of the Chemistry Department at the Pennsylvania State University to pursue the chemistry of diazoparaquinone natural products. Naturally occurring molecules that feature a diazoparaquinone function are quite rare and are among the few examples of organic species that feature a molecule of nitrogen gas as a covalent substituent. Several of these diazoparaquinone-containing species exhibit very potent activity against a range of human cancers, and moreover appear to display a cytotoxicity profile distinct from any other class of anticancer natural products. These observations suggest a unique mechanism-of-action based upon the unusual diazoparaquinone function. The total chemical syntheses of two structurally complex and biologically potent members of this class of compounds are planned. In addition, the design and synthesis of rationally designed analogues of the natural products will be pursued. Together, the natural products and the derived analogues will serve as probes to help elucidate the details of the cytotoxicity mechanism-of-action. Preliminary results implicate both a DNA-damaging sp2 radical and a DNA alkylating orthoquinonemethide electrophile as plausible candidates for the lethal chemical functionality. Successful prosecution of these research objectives may lead to new drug leads, which in turn will impact favorably on the pharmaceutical enterprise in the United States. In addition, this project will provide training for undergraduate and graduate students, including historically underrepresented groups in the sciences, such that these students will be ready to contribute to the scientific enterprise in the United States.

来自美国国家科学基金会化学部化学合成计划的资金将使宾夕法尼亚州立大学化学系的Ken Feldman博士能够从事重氮帕奎酮天然产品的化学研究。天然存在的具有重氮巴喹功能的分子非常罕见，是为数不多的以氮气分子为共价取代基的有机物种之一。其中几个含有重氮帕奎酮的物种对一系列人类癌症表现出非常有效的活性，而且似乎表现出与任何其他类别的抗癌天然产物不同的细胞毒性特征。这些观察结果提示了一种独特的作用机制，这种作用机制基于不寻常的重氮帕奎酮功能。计划对这类化合物中两个结构复杂且具有生物活性的成员进行全化学合成。此外，还将致力于设计和合成设计合理的天然产物类似物。总之，天然产物和衍生类似物将作为探针，帮助阐明细胞毒性作用机制的细节。初步结果表明，DNA损伤的sp2自由基和DNA烷基化邻喹诺亚甲基电泳体都可能是致命化学功能的候选分子。对这些研究目标的成功起诉可能导致新的药物线索，这反过来将对美国的制药企业产生有利影响。此外，该项目将为本科生和研究生提供培训，包括在科学界历史上代表性不足的群体，以便这些学生准备为美国的科学事业做出贡献。