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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >N-Butyl-N-methyl-11-(3'-hydroxy-21', 17'-carbolactone-19'-nor-17'alpha-pregna-1',3', 5'(10')-trien-7'alpha-yl)-undecanamide: an inhibitor of type 2 17beta-hydroxysteroid dehydrogenase that does not have oestrogenic or androgenic activity.
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N-Butyl-N-methyl-11-(3'-hydroxy-21', 17'-carbolactone-19'-nor-17'alpha-pregna-1',3', 5'(10')-trien-7'alpha-yl)-undecanamide: an inhibitor of type 2 17beta-hydroxysteroid dehydrogenase that does not have oestrogenic or androgenic activity.

机译：N-丁基-N-甲基-11-（3'-羟基-21'，17'-carbactactone-19'-nor-17'alpha-pregna-1'，3'，5'（10'）-trien- 7'α-基）-十一碳酰胺：2型17β-羟基类固醇脱氢酶的抑制剂，不具有雌激素或雄激素活性。

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摘要

It is well known that 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) play a key role in the formation and inactivation, from circulating precursors, of several active androgens and oestrogens. These enzymes can thus regulate tumoural cell proliferation in androgen- and oestrogen-dependent cancers. Recently, we discovered that adding a spiro-gamma-lactone to the oestradiol nucleus results in a novel inhibitor of type 2 17beta-HSD, an enzyme that catalyses the interconversions between 4-androstene-3,17-dione and testosterone, and between oestrone and oestradiol. This finding motivated our introducing the spiro-gamma-lactone moiety onto an anti-oestrogenic nucleus. The N-butyl-N-methyl-11-(3'-hydroxy-21', 17'-carbolactone-19'-nor-17'alpha-pregna-1',3', 5'(10')-trien-7'alpha-yl)-undecanamide (4) was then efficiently synthesized and its biological activity was assessed in vitro. Despite the presence of a bulky alkylamide side chain, the spiro-gamma-lactone function conserved its ability to inhibit type 2 17beta-HSD (IC(50) = 0.35 and 0.25 microM, with and without side chain, respectively). Furthermore, the selective inhibition by lactone 4 toward type 2 17beta-HSD (microsomal fraction of human placenta) was demonstrated by the absence of inhibitory activity toward type 1 17beta-HSD (cytosolic fraction of human placenta). Cell proliferation assays indicated that compound 4 had no oestrogenic activity but did show anti-oestrogenic activity on ER(+) cell line ZR-75-1. No androgenic activity could be detected when assayed on the AR(+) cell line Shionogi either. Based on these facts, we report the synthesis of a new steroidal derivative, one that inhibits type 2 17beta-HSD while possessing anti-oestrogenic activity.
机译：众所周知，17β-羟基类固醇脱氢酶（17β-HSD）在循环前体的形成和失活中，起着关键作用，几种活性雄激素和雌激素。因此，这些酶可以调节雄激素和雌激素依赖性癌症中的肿瘤细胞增殖。最近，我们发现向雌二醇核中添加螺-γ-内酯会导致产生新型2型17beta-HSD抑制剂，该酶可催化4-雄甾烯3,17-二酮和睾丸酮以及雌酮之间的相互转化和雌二醇。这一发现促使我们将螺-γ-内酯部分引入抗雌激素核上。 N-丁基-N-甲基-11-（3'-羟基-21'，17'-碳内酯-19'-nor-17'alpha-pregna-1'，3'，5'（10'）-三烯然后有效地合成了-7'α-基）-十一碳酰胺（4），并在体外评估了其生物学活性。尽管存在庞大的烷基酰胺侧链，螺旋-γ-内酯功能仍保留了其抑制2型17beta-HSD的能力（IC（50）= 0.35和0.25 microM，分别带有和不带有侧链）。此外，内酯4对2型17beta-HSD（人胎盘的微粒体部分）的选择性抑制通过对1型17beta-HSD（人胎盘的胞质部分）没有抑制活性来证明。细胞增殖测定表明化合物4没有雌激素活性，但对ER（+）细胞系ZR-75-1表现出抗雌激素活性。在AR（+）细胞系Shionogi上进行检测时也未检测到雄激素活性。基于这些事实，我们报告了一种新的甾族衍生物的合成，该甾族衍生物可抑制2型17beta-HSD，同时具有抗雌激素活性。

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