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首页> 外文期刊>Bioorganic and Medicinal Chemistry >Analogs of 1α,25-dihydroxyvitamin D_3 with high potency in induction of osteoclastogenesis and prevention of dendritic cell differentiation: Synthesis and biological evaluation of 2-substituted 19-norvitamin D analogs
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Analogs of 1α,25-dihydroxyvitamin D_3 with high potency in induction of osteoclastogenesis and prevention of dendritic cell differentiation: Synthesis and biological evaluation of 2-substituted 19-norvitamin D analogs

机译：1α，25-二羟基维生素D_3在诱导破骨细胞形成和防止树突状细胞分化方面具有高效力的类似物：2-取代的19-诺维他命D类似物的合成和生物学评价

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In our previous papers, we found that introduction of a substituent at C(2) into 1α,25-dihydroxy- 19-norvitamin D_3 (2a) caused dramatic changes in binding affinity for the vitamin D receptor (VDR) and in transcriptional activity compared with the parent compound. To investigate the broad biological activity of 2-substituted 19-norvitamin D analogs, we synthesized two new (20S)-2-hydroxyethylidene-19-norvitamin D derivatives (3b and 4b) and a total of 16 A-ring-modified analogs including 3b and 4b were tested for the following in vitro and in vivo biological activities: (1) affinity for the VDR, (2) transcriptional activity, (3) osteoclast formation, (4) bone calcium mobilization in rats, and (5) effects on differentiation of dendritic cells (DCs). The biological effects of the analogs were compared with those of 1α,25-dihydroxyvitamin D_3 (1a) and 2MD, which is being developed for the treatment of osteoporosis. The efficacy of the (205)-19-norvitamin D analogs with 2-hydroxyethylidene, 2-hydroxyethoxy, and 2-methyl moieties (3b, 5b, 6b, and 9b) was more than 10-fold stronger than that of 1a with respect to transcriptional activity, ability to induce osteoclast formation, and ability to inhibit CD86 expression, a marker of mature DCs, and was similar to that of 2MD. The (20S)-2β-hydroxyethoxy derivative 6b was 2 orders of magnitude more active than 1a and approximately twice as potent as 2MD in preventing CD86 production. The 2-epoxy derivatives 7 and 8 were relatively poor ligands for the VDR and exhibited activity lower than that of the natural hormone la.
机译：在我们之前的论文中，我们发现将C（2）处的取代基引入1α，25-二羟基-19-降钙素D_3（2a）中导致与维生素D受体（VDR）的结合亲和力和转录活性相比发生了显着变化与母体化合物。为了研究2-取代的19-norvitamin D类似物的广泛生物活性，我们合成了两种新的（20S）-2-羟乙叉基-19-norvitamin D衍生物（3b和4b）和总共16种经A环修饰的类似物，包括测试了3b和4b的以下体外和体内生物学活性：（1）对VDR的亲和力，（2）转录活性，（3）破骨细胞形成，（4）大鼠骨钙动员和（5）作用对树突状细胞（DC）的分化。将类似物的生物学作用与正在开发用于治疗骨质疏松症的1α，25-二羟基维生素D_3（1a）和2MD进行比较。 （205）-19-norvitamin D类似物具有2-羟基亚乙基，2-羟基乙氧基和2-甲基部分（3b，5b，6b和9b）的功效比1a强10倍以上转录活性，诱导破骨细胞形成的能力以及抑制CD86表达的能力，CD86表达是成熟DC的标志物，与2MD相似。 （20S）-2β-羟基乙氧基衍生物6b的活性比1a高2个数量级，并且在防止CD86产生方面的效力约为2MD的两倍。 2-环氧衍生物7和8是VDR的相对较差的配体，并且表现出比天然激素Ia低的活性。

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