Synthesis and Biological Activity of 2,22-Dimethylene Analogues of 19-Norcalcitriol and Related Compounds

Continuing our search for vitamin D analogues, we explored the modification of the steroidal side chain and inserted a methylene moiety in position C-22 together with either lengthening the side chain or introducing a ring at the terminal end. Our conformational studies confirmed that the presence of a methylene group attached to C-22 restricts the conformational flexibility of the side chain, which can result in changes in biological characteristics of a molecule. All synthesized 1α,25-dihydroxy-2,22-dimethylene-19-norvitamin D3 analogues proved equal to calcitriol in their ability to bind to the vitamin D receptor, and most of them exert significantly higher differentiation and transcriptional activity than calcitriol. The most active compounds were characterized by the presence of an elongated side chain or 26,27-dimethylene bridge. The synthetic strategy was based on the Wittig–Horner coupling of the known A-ring phosphine oxide with the corresponding Grundmann ketones prepared from a 20-epi-Inhoffen-Lythgoe diol derived from vitamin D2.本研究延续了维生素D类似物的研发筛选工作，对甾体侧链进行修饰：在C-22位引入亚甲基基团，同时辅以侧链延长或末端成环操作。构象研究证实，连接于C-22位的亚甲基可限制侧链的构象灵活性，进而改变分子的生物学特性。所有合成的1α,25-二羟基-2,22-二亚甲基-19-去甲维生素D3 (1α,25-dihydroxy-2,22-dimethylene-19-norvitamin D3)类似物，在结合维生素D受体 (vitamin D receptor)的能力上与骨化三醇 (calcitriol)相当；且其中多数类似物的分化诱导活性与转录活性均显著高于骨化三醇。活性最优的化合物均带有延长型侧链或26,27-二亚甲基桥键。本次合成策略依托维蒂希-霍纳尔偶联反应 (Wittig–Horner coupling)：将已知的A环氧化膦，与由维生素D2 (vitamin D2)衍生的20-表-因霍芬-利思格二醇 (20-epi-Inhoffen-Lythgoe diol)制备得到的对应格伦德曼酮 (Grundmann ketones)进行偶联。