Naphthalene-based heterosteroidal molecules

雌激素是一类具有芳香环的类固醇激素系统，它与雌激素受体结合并激活，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。杂原子是人工合成的多环甾体系统，其中一个或多个碳被杂原子取代(S)。由于与天然甾体在结构和拓扑结构上的相似性，杂甾体成为研究的热点，报道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，含关键官能团的杂甾体的合成和立体化学还没有被探索过。Amitabh Jha博士的研究团队已经在生物相关化合物的合成和药物化学方面建立了专业知识。贾哈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人们的极大关注，包括专门从事综合药物发现服务的加拿大公司Paraza Pharma，Inc.的兴趣。Paraza和JHA集团之间的早期讨论导致了NSERC Engage，并随后获得了MITACS Accelerate赠款。在这个拟议的项目中，将开发和优化合成雌激素的杂多环类似物的方法。在24个月的时间里，我们的目标是开发七种不对称合成方法，以合成七种基于萘的类似雌激素的杂甾体。设计的策略包括创新性地使用反应性中间体，如N-酰亚胺离子、氮杂喹酮甲基化合物、给体-受体环丙烷等，以级联方式组装多环核心结构。这项研究将为Paraza提供直接的好处，因为它有望为他们提供一个用于生物评估的密切杂环雌激素同系物的重点文库。这项研究的结果将加强Paraza的研究流水线，包括与类固醇激素受体调节相关的疾病的药物开发。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.