Naphthalene-based heterosteroidal molecules

萘基杂甾体分子

• 批准号: 517705-2017
• 负责人: Jha, Amitabh
• 金额: $ 2.55万
• 依托单位: Acadia University
• 依托单位国家: 加拿大
• 项目类别: Collaborative Research and Development Grants
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=654628
• 关键词: Naphthalene; based; heterosteroidal; molecules

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 estrogen**receptor 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.

雌激素是一类具有芳环的甾体激素系统，与雌激素受体结合并激活雌激素受体，促进各种生理反应，如骨成熟、血脂谱、神经保护作用、生殖功能和乳腺细胞增殖。杂类固醇是人造多环类固醇系统，其中一个或多个碳被杂原子替代。由于与天然类固醇的结构和拓扑相似性，杂甾体是一个激烈的研究课题，报道了新同系物的合成，并揭示了它们所具有的有趣和有用的性质。然而，具有关键官能团和立体化学的杂甾体化合物的合成尚未被探索。Amitabh Jha博士的研究团队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。Jha博士关于姜黄素类似物和选择性雌激素 ** 受体调节剂的研究发现的潜力引起了极大的关注，包括来自帕拉扎制药公司的兴趣，一家专门从事综合药物发现服务的加拿大公司。帕拉扎和Jha集团之间的早期讨论导致了NSERC参与，随后是MITACS加速赠款。在这个项目中，将开发和优化雌激素的杂环类似物的合成方法。在24个月的时间里，我们的目标是开发七种类似雌激素的萘基杂甾体化合物的不对称合成方法。所设计的策略涉及创新性地使用反应性中间体，如N-酰基异丙基离子、氮杂醌甲基化物、供体-受体环丙烷等，以级联方式组装多环核心结构。这项研究将为帕拉扎提供直接的好处，因为它有望为他们提供一个集中的雌激素密切杂环同系物库，用于生物评价。这项研究的结果将加强帕拉扎的研究管道，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。