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

合成器

• 批准号: 6309146
• 负责人: HECTOR F DE LUCA
• 金额: $ 0.75万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-15 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6309146
• 关键词: biological products; biomedical resource; nuclear magnetic resonance spectroscopy

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.

维生素D3是在皮肤中由7-二氢胆固醇合成的 然后在肝脏中羟化成25-羟基维生素D3， 随后在肾脏，到最活跃的荷尔蒙形式 维生素D3，即1？，25-二羟基维生素D3(1？，25-(OH)2D3， 骨化三醇)。已证实1，25-(OH)2D3刺激 肠道钙吸收和动员骨骼中的钙。 近年来，1，25-(OH)2D3在单核细胞中的一个重要作用 人早幼粒白血病细胞(HL-60)的分化 被发现了。最近，1，25-(OH)2D3的20-羟基和烷氧基类似物 已被描述为潜在的药物，并正在接受检查 骨质疏松(如ED-71)。我们准备了2-羟基和2-羟基 19-Nor-1？，25-(OH)2D3及其烷氧基衍生物的类似物。这些 类似物显示出选择性的钙化活性，而且，还显示出 HL-60细胞分化活性高。在我们持续的调查中 关于维生素D分子的构效关系，我们有 还合成了1？烷基和2？？烷基和羟基烷基类似物 19-Nor-1？，25-(OH)2D3。A环片段的构型 用1H、1H COSY 2D谱和1H NOE确定了取代基 差分核磁共振波谱。