Department of Neurosurgery - Harold F. Young Neurosurgical Center and the Massey Cancer Center, Virginia Commonwealth University Medical Center, P.O. Box 980631, 1200 E. Broad Street, Richmond, VA 23298-0631, USA.
Chem Biol Drug Des. 2009 Dec;74(6):625-9. doi: 10.1111/j.1747-0285.2009.00900.x. Epub 2009 Oct 12.
Androstene steroids are metabolites of dehydroepiandrosterone and exist as androstene-diols or -triols in alpha- and beta-epimeric forms based upon the placement of the hydroxyl groups relative to the plane of the Delta(5)cycloperhydrophenanthrene ring. 5-Androstene-3beta,17beta-diol (3beta,17beta-AED) functions to upregulate immunity and the addition of a third hydroxyl group at C-7 in the alpha- or beta-orientation (3beta,7alpha,17beta-AET and 3beta,7beta,17beta-AET, respectively) enhances the immunological activity of the molecule. In contrast, 5-androstene-3beta,17alpha-diol (3beta,17alpha-AED) possesses potent anti-tumor activity. We synthesized a new androstene by adding a third hydroxyl group at C-7 to make 5-androstene-3beta,7alpha,17alpha-triol (3beta,7alpha,17alpha-AET) and compared the anti-tumor activity of this steroid to the four existing androstenes. The results showed that this modification reduced the activity of 3beta,17alpha-AED. The ranking of the anti-tumor activities of these steroids and their IC50 on human glioblastoma and lymphoma cells was: 3beta,17alpha-AED ( approximately 10 microm) > 3beta,7alpha,17alpha-AET ( approximately 30 microm) " 3beta,7alpha,17beta-AET ( approximately 150 microm)> 3beta,7beta,17beta-AET (not achievable) >or= 3beta,17beta-AED (not achievable). 3beta,17alpha-AED and 3beta,7alpha,17alpha-AET induced autophagy in T98G glioblastoma cells and apoptosis in U937 lymphoma cells. These results indicate that the position of the hydroxyl group on C-17 dictates the anti-tumor activity of the androstenes and must be in the alpha-configuration, demonstrating a strict structure-activity relationship.
雄甾烯类甾体是脱氢表雄酮的代谢产物，根据羟基在 Delta(5)环丙二氢菲环平面上的位置，以 α-和 β-差向异构体的形式存在于雄甾烯二醇或三醇中。5-雄甾烯-3β,17β-二醇（3β,17β-AED）具有上调免疫功能的作用，在 C-7 位增加第三个羟基，无论是在 α-还是 β-构型（分别为 3β,7α,17β-AET 和 3β,7β,17β-AET），都能增强分子的免疫活性。相比之下，5-雄甾烯-3β,17α-二醇（3β,17α-AED）具有很强的抗肿瘤活性。我们通过在 C-7 位增加第三个羟基合成了一种新的雄甾烯，得到 5-雄甾烯-3β,7α,17α-三醇（3β,7α,17α-AET），并比较了这种甾体的抗肿瘤活性与现有的四种雄甾烯。结果表明，这种修饰降低了 3β,17α-AED 的活性。这些甾体的抗肿瘤活性及其对人胶质母细胞瘤和淋巴瘤细胞的 IC50 排序为：3β,17α-AED（约 10 μM）>3β,7α,17α-AET（约 30 μM）>3β,7α,17β-AET（约 150 μM）>3β,7β,17β-AET（不可达）≥3β,17β-AED（不可达）。3β,17α-AED 和 3β,7α,17α-AET 在 T98G 胶质母细胞瘤细胞中诱导自噬，在 U937 淋巴瘤细胞中诱导凋亡。这些结果表明，C-17 位上羟基的位置决定了雄甾烯的抗肿瘤活性，必须处于 α-构型，表现出严格的结构-活性关系。
