抗骨质疏松药物及氮芥类抗癌药物的设计与合成-有机化学专业毕业论文.docxVIP

摘要中文摘要 摘要 中文摘要 内源性雌激素不但对女性性器官、乳腺及其它性征的发育和保持有重要的作 用，而且对人体其它组织如骨骼、心血管系统、神经系统的生长发育和保持也十分 重要。妇女绝经后，由于雌激素的下降或缺乏，常常导致骨质疏松、心血管疾病、 雌激素依赖型癌症等许多绝经后妇女综合症的发生刈缶床上～般采用雌激素替代疗 法或者荷尔蒙替代疗法来治疗绝经后综合症，虽然疗效尚可，但有严重的副作用。 解决雌激素替代疗法的安全问题主要有两条可行的方法：一是利用骨骼和生殖 器官上的雌激素受体的差异，发展选择性雌激素受体调节剂(SERMs)。另一个解 决途径是研制骨靶向药物，利用骨靶向载体转运其他药物治疗骨质疏松，减少副作 用。 为了寻找安全、商效的抗骨质疏松和乳腺癌药物，本论文完成了以下二方圆的 工作： 1．设计合成了具有趋骨性的雷洛昔芬和双膦酸的拼合物，化合物的体内骨质疏松 筛选结果表明所设计的化台物均能抑制OVX模型小鼠的骨流失，其中2个化 合物有较好的效果，显示一定的骨质疏松症治疗前景。 2．设计合成了60个未见文献报道的茚并吲哚类选择性雌激素受体调节剂化合物， 其中44个为最终产物，并通过核磁、质谱、元素分析等进行结构确证。部分化 合物的体外核受体实验和体内抗骨质疏松实验正在进行中。 3．探索了用以治疗激素依赖型癌症的新型氮芥类化合物的设计与合成。初步抗肿 瘤筛选结果表明效果不是很理想。 关键词：骨质疏松选择性雌激素受体调节剂骨靶向茚并11，2南】吲哚氮芥 Ⅳ A A bSfract Abstrfltet Endocrine estrogens play impoaant roles not only in the development and function ofthe reproductive system and the female mammary gland but also in other tissues such as bone，cardiovascular system and the development and maintenance of neural system． Because of estrogen deficiency in postmenopausal women，it often leads to the occurrence of many postmenopausal syndromes such aS osteoporosis，cardiovascular effects and estrogen—dependent cancel etc．Estrogen replacement therapy／ERT or hormone replacement therapy／HRT are clinically used to prevent the postmenopausal syndrome，however，with serious side effects． To solve the problem of safety,two approaches can be taken．One approach is to make estrogens that can act as agonist in bone，but as antagonist in reproductive organs． Examples are so—called selective estrogen receptor modulators(SERMs)．The second approach is to make bone—targeted agents，which call specifically deliver drugs to osseous tissue，reducing side effects． To find more safe and potent anti—osteoporosis and anticancer agents，We accomplished three parts ofwork as follows： 1·Design and synthesis of bone-targeted Ratoxifene—Bisphosphonate hybrids．The results of screening in OVX mice model showed that the compounds can inhibit bone toss．Two of them seem worthy for further studies for the prevention of osteoporosis