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目的 研究系列苯并二氢吡喃化合物的构效关系 ,为设计优良的绝经后骨质疏松症防治药物提供理论依据。方法 在综合考察雷洛昔芬和异丙氧基异黄酮的基础上 ,设计合成一系列苯并二氢吡喃化合物 ,从整体水平考察化合物A对去卵巢大鼠骨质疏松的影响 ,从细胞水平研究C单独给药以及与雌二醇联合给药对人成骨细胞株HOSTE85增殖的影响 ,并均在 0 1μmol·L-1水平考察比较化合物BE对HOSTE85增殖的影响。结果 化合物A可一定程度对抗去卵巢大鼠骨质疏松症。C( 1 0nmol·L-1,0 1μmol·L-1)对HOSTE85具有显著增殖作用 ,C与雌二醇联合给药显著拮抗雌二醇对HOSTE85的增殖作用 ,故C可能为雌激素受体的部分激动剂。C、D( 0 1μmol·L-1)对HOSTE85具有显著增殖作用。结论 以A作为母体化合物 ,侧链引入碱性基团 ,对其结构修饰设计抗绝经后骨质疏松症药物是可行的。
Objective To study the structure-activity relationship of chroman compounds and to provide a theoretical basis for the design of excellent anti-osteoporosis drugs. Methods Based on a comprehensive study of raloxifene and isopropoxy isoflavone, a series of chroman compounds were designed and synthesized. The effects of compound A on osteoporosis in ovariectomized rats were investigated. Level study C alone and combined with estradiol on the proliferation of human osteoblast cell line HOSTE85, and at the level of 0 1μmol·L-1 study compound BE on HOSTE85 proliferation. Results Compound A can antagonize ovariectomized rats to some extent. C (10nmol·L-1, 1μmol·L-1) had a significant proliferative effect on HOSTE85. Combined administration of C and estradiol significantly inhibited the proliferation of HOSTE85 induced by estradiol, so C may be an estrogen receptor Partial agonist. C, D (0 1μmol·L-1) had a significant proliferative effect on HOSTE85. Conclusion It is feasible to design anti-postmenopausal osteoporosis drugs by using A as the parent compound and introducing basic groups into the side chains.