靶向雌激素受体非核效应信号通路特异性小分子化合物的设计、合成及其对心血管的选择性保护作用研究

The diverse effects of estrogens provide many opportunities for the development of important pharmaceutical agents, but they also pose challenges in terms of achieving desired patterns of selectivity, e.g. breast cancer and endometrial cancer. Traditionally, this selectivity has been sought in two principal ways. Estrogen action in regulating gene transcription has been attributed to estrogen binding to nuclear estrogen receptor (ER). However, there has been increasing evidence for rapid effects of estrogen in various cell types that is attributed to extranuclear-initiated actions (“nongenomic”) of estrogen binding to extranuclear estrogen receptor. While the field has largely focused on these nuclear-initiated roles (“genomic”) of the ERs involving direct effects on transcription, more attention is now being paid to the long-recognized “rapid, non-transcriptional” effects of estrogens. The great challeging for study the molecular mechanism of the nongenomic pathway is to distinct this signaling from the corresponding genomic one. These extranuclear-initiated actions of ER, which involve rapid effects on kinase activation etc, do not require transcription, and they result from signaling processes that originate in the cytoplasm and possibly in the membrane. Although extranuclear ER action can ultimately lead to altered patterns of transcription, the central point is that this signaling cascade involves the coupling of ligand-ER complexes with other partners (principally G-proteins and kinases) in interactions that are distinct from the signaling pathway and interaction targets that underlie nuclear-initiated ER action. But attempts to achieve selective estrogen action by the development of pharmaceuticals that are pathway selective are still at an early stage. Thus, we will develop carefully designed small molecules that provide potent and effective cardiovascular protection without breast cancer and reproductive stimulatory effects. Through a process of structural alteration of estrogenic ligands that was designed to preserve their essential chemical and physical features but greatly reduced their binding affinity for ERs, we will obtain pathway preferential estrogens, which interact with ERs to activate the extranuclear-initiated signaling pathway preferentially over the nuclear-initiated pathway. Meanwhile, the use of the novel dual-functional ligands as potential imaging probes for extranuclear estrogen receptor and related mechanism studies will also be investigated. Medically, such agents could provide protection during periods of acute vascular injury of menopausal syndrome without reproductive stimulatory effects. This study will lay foundations for development of novel SERMs targeting extranuclear estrogen receptor with potential therapeutic and/or imaging properties.

雌激素调节着许多重要的生理过程，并且能维持生殖系统内外多种靶点细胞的功能，然而雌激素也可能会诱发乳腺癌和子宫内膜癌。传统认为雌激素是通过与核雌激素受体（Estrogen receptor, ER）结合来产生作用而启动基因转录，但是雌激素也可以通过快速激活核外受体启动的激酶级联反应而具有非基因组作用。越来越多的证据显示雌激素在各种细胞中的快速作用属于非基因组信号，但如何将这些作用与其基因组通路分开，以增加雌激素的有利影响，减弱其不利影响，是目前面临的挑战之一。本研究工作是基于结构-导向的药物设计策略，优化有效的小分子以获取对ER非核效应通路的选择性激活但不会刺激生殖系统，且具有心血管保护作用的药物先导化合物，以最大程度地降低更年期激素替代疗法的风险。此外，将探索兼具靶向非核ER分子影像功能和心血管保护活性的双功能小分子探针研究。本课题的实施为开发更有效的选择性雌激素受体调节剂提供技术创新。

越来越多的证据显示雌激素在各种细胞中的快速作用属于非基因组信号，但如何将这些作用与其基因组通路分开，以增加雌激素的有利影响并减弱其不利影响，是目前面临的挑战之一。本研究工作是优化有效的小分子以获取对ER非核效应通路的选择性激活但不会刺激生殖系统，且具有心血管保护作用的药物先导化合物，以最大程度地降低更年期激素替代疗法的风险。本项目基于结构多样性-导向的药物设计策略，设计、合成了多个系列结构新颖、多样的具有亚胺、酞嗪类母核、双环[2.2.1]庚-2-烯骨架（OBHS）及杂环核心结构的靶向非核ER配体。研究了这些配体对ER非基因组信号通路的选择性激活及构效关系（SAR）。从而有针对地对先导化合物的结构进行进一步的优化，发现了数个新型的具有选择性激活ER非基因组信号通路的药物先导化合物，但对核ER没有结合及效应能力。初步机制研究表明，部分化合物是通过激活mTOR信号通路，Ser118的磷酸化，以及增加NOS活性来发挥作用，但不会刺激生殖系统，以期具有良好心血管保护作用。此外，设计并合成了靶向非核ER分子探针并探索了其影像功能。在研期间发表SCI论文17篇，获湖北省科技进步奖二等奖1项，获批中国专利10项，取得了较为丰硕的成果。

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