Eskitis Institute for Cell and Molecular Therapies, Griffith University, 170 Kessels Road, Nathan, Queensland 4111, Australia.
J Med Chem. 2010 Apr 8;53(7):2913-26. doi: 10.1021/jm901888x.
The contribution of membrane-bound carbonic anhydrases (CAs) to hypoxic tumor growth and progression in cancer implicates cancer-associated CAs as a promising drug target for oncology. In this paper, we present a new class of sulfonamide-linked neoglycoconjugate that was designed to selectively target and inhibit the extracellular domains of the cancer-relevant CA isozymes. We describe the application of novel, yet straightforward, chemistry toward the synthesis of inhibitors that comprise both S-glycosyl sulfenamides and S-glycosyl sulfonamides. We also present the CA inhibition profile of our new neoglycoconjugates, more specifically a library of 30 compounds (3-32) that were designed to optimize both SAR (structure-activity relationship) and SPR (structure-property relationship) characteristics. We show that our approach produces neutral, water-soluble, and potent inhibitors (K(i)s in the low nanomolar range) that target cancer-associated CAs.
膜结合碳酸酐酶（CA）对缺氧肿瘤生长和肿瘤进展的贡献表明，肿瘤相关 CA 是肿瘤学中一个很有前途的药物靶点。在本文中，我们提出了一类新的磺酰胺连接的糖基化缀合物，旨在选择性靶向和抑制与癌症相关的 CA 同工酶的细胞外结构域。我们描述了一种新颖而简单的化学方法，用于合成包含 S-糖基半胱氨酸亚砜酰胺和 S-糖基磺酰胺的抑制剂。我们还介绍了我们新的糖基化缀合物的 CA 抑制谱，更具体地说，是一个包含 30 个化合物（3-32）的文库，旨在优化 SAR（结构-活性关系）和 SPR（结构-性质关系）特征。我们表明，我们的方法产生了中性、水溶性和有效的抑制剂（K(i) 值在纳摩尔范围内），这些抑制剂针对与癌症相关的 CA。
