Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff, CF10 3NB, Wales, United Kingdom.
J Med Chem. 2010 Apr 8;53(7):2757-65. doi: 10.1021/jm901757t.
The zinc-ejecting aldehyde dehydrogenase (ALDH) inhibitory drug disulfiram (DSF) was found to be a breast cancer-associated protein 2 (BCA2) inhibitor with potent antitumor activity. We herein describe our work in the synthesis and evaluation of new series of zinc-affinic molecules to explore the structural requirements for selective BCA2-inhibitory antitumor activity. An N(C=S)S-S motif was found to be required, based on selective activity in BCA2-expressing breast cancer cell lines and against recombinant BCA2 protein. Notably, the DSF analogs (3a and 3c) and dithio(peroxo)thioate compounds (5d and 5f) were found to have potent activity (submicromolar IC(50)) in BCA2 positive MCF-7 and T47D cells but were inactive (IC(50) > 10 microM) in BCA2 negative MDA-MB-231 breast cancer cells and the normal breast epithelial cell line MCF10A. Testing in the isogenic BCA2 +ve MDA-MB-231/ER cell line restored antitumor activity for compounds that were inactive in the BCA2 -ve MDA-MB-231 cell line. In contrast, structurally related dithiocarbamates and benzisothiazolones (lacking the disulfide bond) were all inactive. Compounds 5d and 5f were additionally found to lack ALDH-inhibitory activity, suggestive of selective E3 ligase-inhibitory activity and worthy of further development.
锌排出型醛脱氢酶 (ALDH) 抑制剂戒酒硫 (DSF) 被发现是一种乳腺癌相关蛋白 2 (BCA2) 抑制剂，具有很强的抗肿瘤活性。我们在此描述了我们在合成和评估新系列锌亲和分子方面的工作，以探索选择性 BCA2 抑制抗肿瘤活性的结构要求。基于在表达 BCA2 的乳腺癌细胞系和重组 BCA2 蛋白中的选择性活性，我们发现需要一个 N(C=S)S-S 基序。值得注意的是，DSF 类似物 (3a 和 3c) 和二硫(过氧)硫代酯化合物 (5d 和 5f) 对 BCA2 阳性 MCF-7 和 T47D 细胞具有很强的活性 (亚微摩尔 IC(50))，但对 BCA2 阴性 MDA-MB-231 乳腺癌细胞和正常乳腺上皮细胞系 MCF10A 无活性 (IC(50)>10 微摩尔)。在同基因 BCA2 +ve MDA-MB-231/ER 细胞系中的测试恢复了在 BCA2 -ve MDA-MB-231 细胞系中无活性的化合物的抗肿瘤活性。相比之下，结构相关的二硫代氨基甲酸盐和苯并异噻唑酮 (缺乏二硫键) 均无活性。化合物 5d 和 5f 还被发现缺乏 ALDH 抑制活性，提示其具有选择性 E3 连接酶抑制活性，值得进一步开发。
