Diazoparaquinone Natural Products Chemistry

来自美国国家科学基金会化学部化学合成项目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喹酮天然产物的化学研究。具有重氮帕醌功能的天然分子非常罕见，并且是有机物种中为数不多的以氮气分子作为共价取代基的例子。这些含有重氮帕喹酮的物种中有几种对一系列人类癌症表现出非常有效的活性，而且似乎显示出与任何其他类型的抗癌天然产物不同的细胞毒性。这些观察结果表明，基于不寻常的重氮帕喹酮功能，具有独特的作用机制。计划了这类化合物的两个结构复杂且生物活性强的成员的总化学合成。此外，设计和合成合理设计的天然产物类似物将继续进行。天然产物和衍生类似物将共同作为探针，帮助阐明细胞毒性作用机制的细节。初步结果表明，DNA损伤sp2自由基和DNA烷基化正醌甲醚亲电试剂可能是致命化学功能的候选物质。这些研究目标的成功实施可能会带来新的药物线索，这反过来又会对美国的制药企业产生有利的影响。此外，该项目将为本科生和研究生提供培训，包括历史上在科学领域代表性不足的群体，使这些学生准备好为美国的科学事业做出贡献。

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.