SYNTH & BIOL ACTIVITY OF 2 SUBSTITUTED ANALOGS OF 1,25 DIHYDROXY 1 9 NORVITAMIN

维生素D3在皮肤中由7-二氢胆固醇合成 然后在肝脏中羟基化为25-羟基维生素D3， 随后在肾脏，最活跃的激素形式， 维生素D3，即1？，25-二羟基维生素D3（1？，25-（OH）2D3， 骨化三醇）。 据了解，1？25-（OH）2D 3刺激 肠钙吸收和动员钙从骨。 最近，一个重要的功能1？，单核细胞中的25-（OH）2D 3 人早幼粒细胞白血病细胞（HL-60）的分化已经被 发现了 最近，1 R的20-羟基和烷氧基类似物，25-（OH）2D3 已经被描述并正在被研究作为潜在的药物， 骨质疏松症（如艾德-71）。 我们准备了两个？- 2？羟基 19-去甲-1？的类似物，25-（OH）2D 3及其烷氧基衍生物。 这些 类似物表现出选择性的钙离子活性，而且， 高HL-60分化活性。 在我们的调查中 维生素D分子的结构-活性关系，我们有 还合成了1？2、？的烷基和羟烷基类似物 19-nor-1？25-（OH）2D3。 A环片段的重定向 用1H、1HCOSY二维谱和1HNOE谱确定了取代基 差示核磁共振谱

Vitamin D3 is synthesized in the skin from 7-dihydrocholesterol and then hydroxylated to 25-hydroxyvitamin D3 in the liver and, subsequently in the kidney, to the most active hormonal form of vitamin D3, namely, 1?,25-dihydroxy vitamin D3 (1?,25-(OH)2D3, calcitriol). It has been established that 1?,25-(OH)2D3 stimulates intestinal calcium absorption and mobilizes calcium from bone. Recently, an important function of 1?,25-(OH)2D3 in monocytic differentiation of human promyelocytic leukemia cells (HL-60) has been discovered. Recently, 20-hydroxy and alkoxy analogs of 1?,25-(OH)2D3 have been described and are being examined as potential drugs for osteoporosis (e.g. ED-71). We prepared both 2?- and 2?-hydroxy analogs of 19-nor-1?,25-(OH)2D3 and their alkoxy derivatives. These analogs exhibited selective calcemic activity and, moreover, showed high HL-60 differentiation activity. In our continuing investigation of structure-activity relationship of the vitamin D molecule, we have also synthesized 1?- and 2??-alkyl and hydroxyalkyl analogs of 19-nor-1?,25-(OH)2D3. Configurations of the A-ring fragment substituents were determined by 1H, 1H COSY 2D spectra and 1H NOE difference NMR spectroscopy.