Leese Mathew P, Jourdan Fabrice L, Gaukroger Keira, Mahon Mary F, Newman Simon P, Foster Paul A, Stengel Chloe, Regis-Lydi Sandra, Ferrandis Eric, Di Fiore Anna, De Simone Giuseppina, Supuran Claudiu T, Purohit Atul, Reed Michael J, Potter Barry V L
Department of Pharmacy and Pharmacology, University of Bath, Bath, UK.
J Med Chem. 2008 Mar 13;51(5):1295-308. doi: 10.1021/jm701319c. Epub 2008 Feb 9.
The synthesis, SAR, and preclinical evaluation of 17-cyanated 2-substituted estra-1,3,5(10)-trienes as anticancer agents are discussed. 2-Methoxy-17beta-cyanomethylestra-1,3,5(10)-trien-3-ol ( 14), but not the related 2-ethyl derivative 7, and the related 3- O-sulfamates 8 and 15 display potent antiproliferative effects (MCF-7 GI 50 300, 60 and 70 nM, respectively) against human cancer cells in vitro. Investigation of the SAR reveals that a sterically unhindered hydrogen bond acceptor attached to C-17 is most likely key to the enhanced activity. Compound 8 displayed significant in vitro antiangiogenic activity, and its ability to act as a microtubule disruptor was confirmed. Inhibitory activity of the sulfamate derivatives against steroid sulfatase and carbonic anhydrase II (hCAII) was also observed, and the interaction between 15 and hCAII was investigated by protein crystallography. The potential of these multimechanism anticancer agents was confirmed in vivo, with promising activity observed for both 14 and 15 in an athymic nude mouse MDA-MB-231 human breast cancer xenograft model.
讨论了17-氰基-2-取代estra-1,3,5(10)-三烯作为抗癌剂的合成、构效关系（SAR）和临床前评价。2-甲氧基-17β-氰基甲基estra-1,3,5(10)-三烯-3-醇（14），而非相关的2-乙基衍生物7，以及相关的3-O-氨基磺酸酯8和15在体外对人癌细胞显示出强效的抗增殖作用（MCF-7的GI50分别为300、60和70 nM）。构效关系研究表明，连接在C-17上的空间位阻较小的氢键受体很可能是活性增强的关键。化合物8在体外显示出显著的抗血管生成活性，并且其作为微管破坏剂的能力得到了证实。还观察到氨基磺酸酯衍生物对类固醇硫酸酯酶和碳酸酐酶II（hCAII）的抑制活性，并通过蛋白质晶体学研究了15与hCAII之间的相互作用。这些多机制抗癌剂的潜力在体内得到了证实，在无胸腺裸鼠MDA-MB-231人乳腺癌异种移植模型中，14和15均观察到有前景的活性。
