Carbonic anhydrase inhibitors: Hypoxia-activatable sulfonamides incorporating disulfide bonds that target the tumor-associated isoform IX
Carbonic anhydrase inhibitors: Hypoxia-activatable sulfonamides incorporating disulfide bonds that target the tumor-associated isoform IX
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DOI：
10.1021/jm060531j
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发表时间：
2006-09-07
影响因子：
7.3
通讯作者：
Supuran, Claudiu T.
中科院分区：
文献类型：
--
作者：
De Simone, Giuseppina;Vitale, Rosa Maria;Supuran, Claudiu T.
报道了一种针对肿瘤相关亚型的生物还原、低氧激活的碳酸酐酶(CA，EC 4.2.1.1)抑制剂的设计方法。制备了含有3，3‘-dithiodipropionamide/2，2’-dithiodibenzamido部分的磺胺类化合物，并在低氧肿瘤中存在的条件下通过酶/化学还原生成硫醇。最有希望的化合物4-(2-巯基苯基甲酰胺)苯磺酰胺在与HCa II的加合物中，二硫键对Hca IX的K-I为653 nm(还原形式为9.1 nm)，X-射线晶体结构表明该缓蚀剂与Gln92、Val121、Phe131、Leu198、Thr199、Thr200、Pro201和Pro202发生了良好的相互作用，而磺酰基则与锌离子配位。与Hca IX的加合物中保留了相同的相互作用，但此外，抑制物的SH部分与Gln67的酰胺氮之间存在氢键，这可能解释了肿瘤相关同工酶的抑制效果几乎是胞浆同工酶的2倍。
An approach for designing bioreductive, hypoxia-activatable carbonic anhydrase ( CA, EC 4.2.1.1) inhibitors targeting the tumor-associated isoforms is reported. Sulfonamides incorporating 3,3'-dithiodipropionamide/2,2'-dithiodibenzamido moieties were prepared and reduced enzymatically/chemically in conditions present in hypoxic tumors, leading to thiols. The X-ray crystal structure of the most promising compound, 4-( 2-mercaptophenylcarboxamido) benzenesulfonamide, which as disulfide showed a K-I against hCA IX of 653 nM ( in reduced form of 9.1 nM), in adduct with hCA II showed the inhibitor making favorable interactions with Gln92, Val121, Phe131, Leu198, Thr199, Thr200, Pro201, and Pro202, whereas the sulfamoyl moiety was coordinated to the Zn2+ ion. The same interactions were preserved in the adduct with hCA IX, but in addition, a hydrogen bond between the SH moiety of the inhibitor and the amide nitrogen of Gln67 was evidenced, which may explain the almost 2 times more effective inhibition of the tumor-associated isozyme over the cytosolic isoform.