Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia.
J Med Chem. 2011 Oct 13;54(19):6905-18. doi: 10.1021/jm200892s. Epub 2011 Sep 2.
Carbonic anhydrase (CA) enzymes, specifically membrane-bound isozymes CA IX and CA XII, underpin a pH-regulating system that enables hypoxic tumor cell survival and proliferation. CA IX and XII are implicated as potential targets for the development of new hypoxic cancer therapies. To date, only a few small molecules have been characterized in CA-relevant cell and animal model systems. In this paper, we describe the development of a new class of carbohydrate-based small molecule CA inhibitors, many of which inhibit CA IX and XII within a narrow range of low nanomolar K(i) values (5.3-11.2 nM). We evaluate for the first time carbohydrate-based CA inhibitors in cell-based models that emulate the protective role of CA IX in an acidic tumor microenvironment. Our findings identified two inhibitors (compounds 5 and 17) that block CA IX-induced survival and have potential for development as in vivo cancer cell selective inhibitors.
碳酸酐酶（CA）酶，特别是膜结合同工酶 CAIX 和 CAXII，为支持低氧肿瘤细胞存活和增殖的 pH 调节系统提供支持。CAIX 和 CAXII 被认为是开发新的缺氧癌症治疗方法的潜在靶点。迄今为止，仅在 CA 相关的细胞和动物模型系统中对少数几种小分子进行了表征。在本文中，我们描述了一类新型碳水化合物小分子 CA 抑制剂的开发，其中许多抑制剂在低纳摩尔范围内抑制 CAIX 和 CAXII（5.3-11.2 nM）。我们首次在细胞模型中评估了基于碳水化合物的 CA 抑制剂，这些模型模拟了 CAIX 在酸性肿瘤微环境中的保护作用。我们的研究结果确定了两种抑制剂（化合物 5 和 17），它们可以阻断 CAIX 诱导的存活，并且具有作为体内癌细胞选择性抑制剂开发的潜力。
