Center for Chemistry, Institute of Chemistry, Technology and Metallurgy, University of Belgrade, Studentski trg 12-16, P. O. Box 473, 11001 , Belgrade, Republic of Serbia.
Mol Divers. 2013 Aug;17(3):547-61. doi: 10.1007/s11030-013-9455-9. Epub 2013 Jun 9.
The reactions of 21-hydroxyprogesterone with Lawesson's reagent in toluene or [Formula: see text] gave four P-heterocyclic androst-4-ene derivatives (two tautomeric pairs): 4-(3-thioxoandrost-4-en-17[Formula: see text]-yl)-1,3,2-oxathiaphosphole-2- sulfide (2), 4-(3-thioxoandrost-4-en-17[Formula: see text]-ylidene)-1,3,2-oxathiaphospholane-2-sulfide (3), 4-(3-oxoandrost-4-en-17[Formula: see text]-yl)-1,3,2-oxathiaphosphole-2-sulfide (4), and 4-(3-oxoandrost-4-en-17[Formula: see text]-ylidene)-1,3,2- oxathiaphospholane-2-sulfide (5). The structures of all novel 17-substituted steroids were elucidated from their analytic and spectral data (HRMS, IR, 1D NMR and 2D NMR-HSQC, HMBC, NOESY, COSY). The detailed NMR analysis for all compounds revealed the presence of two pairs of signals in approx. 8:2 ratio indicating the existence of two diastereoisomers (a and b) with different configurations at the phosphorus atom. A parallel analysis of heteronuclear 2D [Formula: see text]-[Formula: see text] spectra (HSQC and HMBC) and homonuclear 2D spectra (NOESY and COSY) enabled complete [Formula: see text] and [Formula: see text] assignments of each isomer and provided evidence for the preferred configuration on phosphorus atom. Cytotoxic activity in vitro was tested against four tumor cell lines (human cervix carcinoma HeLa cells, chronic myelogenous leukemia K-562 and two human breast carcinoma MDA-MB-361 and MDA-MB-453 cells). Compounds 3a,b and 4a,b showed a poor activity against HeLa and MDA-MB-453 cell lines, while against MDA-MB-361 cell line, all tested compounds exerted very weak cytotoxic effect. All compounds exerted moderate activity against K562 cells. Antimicrobial activity against Gram-positive, Gram-negative bacteria and fungal cells, and toxicity to brine shrimp Artemia salina were evaluated. All tested compounds showed strong antifungal activity.
21-羟孕酮与劳森试剂在甲苯或二甲亚砜中的反应生成了四个 P-杂环雄甾-4-烯衍生物（两对互变异构体）：4-(3-硫代雄甾-4-烯-17β-基)-1,3,2-氧杂噻磷杂环戊烷-2-硫醚（2）、4-(3-硫代雄甾-4-烯-17β-亚甲基)-1,3,2-氧杂噻磷杂环戊烷-2-硫醚（3）、4-(3-氧代雄甾-4-烯-17β-基)-1,3,2-氧杂噻磷杂环戊烷-2-硫醚（4）和 4-(3-氧代雄甾-4-烯-17β-亚甲基)-1,3,2-氧杂噻磷杂环戊烷-2-硫醚（5）。所有新型 17-取代甾体的结构均通过其分析和光谱数据（高分辨质谱、红外、一维 NMR 和二维 NMR-HSQC、HMBC、NOESY、COSY）阐明。对所有化合物的详细 NMR 分析表明，在约 8:2 的比例下存在两对信号，表明磷原子的不同构型存在两种非对映异构体（a 和 b）。对异核二维 [Formula: see text]-[Formula: see text] 光谱（HSQC 和 HMBC）和同核二维光谱（NOESY 和 COSY）的平行分析使每个异构体的 [Formula: see text] 和 [Formula: see text] 完全分配，并为磷原子上的优选构型提供了证据。体外细胞毒性活性针对四种肿瘤细胞系（人宫颈癌细胞 HeLa 细胞、慢性髓性白血病 K-562 细胞和两种人乳腺癌 MDA-MB-361 细胞和 MDA-MB-453 细胞）进行了测试。化合物 3a,b 和 4a,b 对 HeLa 和 MDA-MB-453 细胞系的活性较差，而对 MDA-MB-361 细胞系，所有测试化合物均表现出非常弱的细胞毒性作用。所有化合物对 K562 细胞均表现出中等活性。评估了对革兰氏阳性、革兰氏阴性细菌和真菌细胞的抗菌活性以及对盐水虾卤虫 Artemia salina 的毒性。所有测试化合物均表现出强烈的抗真菌活性。
