Naphthalene-based heterosteroidal molecules

雌激素是甾体激素系统的一类，具有芳香环，与雌激素受体结合并激活雌激素受体，促进多种生理反应，如骨成熟、血脂谱、神经保护作用、生殖功能和乳腺细胞增殖。杂甾体是人造的多环甾体系统，其中一个或多个碳被杂原子取代。由于与天然类固醇在结构和拓扑结构上的相似性，异甾体是一个备受关注的研究课题，报告了新的同系物的合成，并揭示了它们所具有的有趣和有用的性质。然而，含关键官能团的异甾体的合成和立体化学尚未进行研究。Amitabh Jha博士的研究团队在生物相关化合物和药物化学合成方面建立了专业知识。Jha博士在姜黄素类似物和选择性雌激素受体调节剂方面的研究成果的潜力引起了极大的关注，包括Paraza Pharma， Inc.（一家专门从事综合药物发现服务的加拿大公司）的兴趣。Paraza和Jha集团之间的早期讨论导致了NSERC参与，随后获得了MITACS加速资助。本课题将开发和优化雌激素杂多环类似物的合成方法。在24个月的时间里，我们的目标是开发7种类似雌激素的萘基异类固醇的不对称合成方法。设计的策略包括创新地使用反应性中间体，如n -酰基铵离子、氮杂醌方法、供体-受体环丙烷等，以级联方式组装多环核心结构。该研究将为Paraza提供一个雌激素近杂环同源物的重点文库，用于生物评价。这项研究的结果将加强Paraza的研究管道，包括类固醇激素受体调节相关疾病的药物开发。该项目还将为对有机合成感兴趣的HQP提供重要的培训机会。

Estrogens, a category of the steroidal hormone system having an aromatic ring, bind with and activate the estrogen receptors promoting a variety of physiological responses such as bone maturation, blood lipid profile, neuroprotective effects, reproductive functions and breast cell proliferation. Heterosteroids are man-made polycyclic steroidal systems where one or more carbons are replaced by heteroatom(s). Owing to the structural and topological similarity with natural steroids, heterosteroids are a subject of intense research that reports syntheses of new congeners and unveils interesting and useful properties that they possess. However, synthesis of heterosteroids bearing key functional groups and stereochemistry have not be explored. Dr. Amitabh Jha's research team has established expertise in synthesis of biologically relevant compounds and medicinal chemistry. The potential of Dr. Jha's research findings on curcumin analogs and selective estrogenreceptor modulators attracted significant attention, including interest from Paraza Pharma, Inc., a Canadian company that specializes in integrated drug discovery services. Early discussions between Paraza and the Jha Group led to an NSERC Engage and subsequently a MITACS Accelerate grant. In this proposed project, methods will be developed and optimized for the synthesis of heteropolycylic analogs of estrogen. Over a period of 24 months, our goal is to develop asymmetric synthetic methodologies for seven naphthalene-based heterosteroids resembling estrogen. The designed strategy involves the innovative use of reactive intermediates such as N-acyliminium ions, azaquinone methides, donor-acceptor cyclopropanes, etc. in a cascade fashion to assemble the polycyclic core structure. This research will provide direct benefit to Paraza as it is expected to provide them with a focused library of close heterocyclic congeners of estrogen for bioevaluation. The results of this study will strengthen Paraza's research pipeline to include drug development for diseases related to modulation of steroidal hormone receptors. This project will also enable significant training opportunities for HQP interested in organic synthesis.