Synthesis and biological evaluation of non-glucose glycoconjugated N-hydroyxindole class LDH inhibitors as anticancer agents.
Synthesis and biological evaluation of non-glucose glycoconjugated N-hydroyxindole class LDH inhibitors as anticancer agents.
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DOI：
10.1039/c5ra00946d
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发表时间：
2015
期刊：
影响因子：
3.9
通讯作者：
Minutolo F
中科院分区：
文献类型：
--
作者：
Di Bussolo V;Calvaresi EC;Granchi C;Del Bino L;Frau I;Lang MC;Tuccinardi T;Macchia M;Martinelli A;Hergenrother PJ;Minutolo F
人乳酸脱氢酶A(LDH-A)抑制剂是一种很有前途的抗癌药物。到目前为止，具有细胞活性的LDH-A抑制剂的开发被证明是特别具有挑战性的，因为这种酶的活性部位很窄，而且是高度极性的。在最近的过去，我们能够开发出一种基于N-羟基吲哚的葡萄糖结合的LDH-A抑制剂，旨在利用癌细胞表达的糖亲和力(Warburg效应)。在这里，我们描述了通过在其结构中插入α-D-甘露糖、β-D-半乳糖或β-N-乙酰-D-氨基葡萄糖部分来对这类抑制剂的糖部分进行结构调节。报道了它们的立体特异性化学合成，包括底物依赖的立体特异性糖基化步骤，以及它们在减少癌细胞中乳酸产生和增殖方面的生物活性。有趣的是，α-D-甘露糖结合物在细胞检测中表现出最好的性质，在癌细胞中显示出有效的抗糖酵解和抗增殖活性。
Inhibitors of human lactate dehydrogenase A (LDH-A) are promising therapeutic agents against cancer. The development of LDH-A inhibitors that possess cellular activities has so far proved to be particularly challenging, since the enzyme’s active site is narrow and highly polar. In the recent past, we were able to develop a glucose-conjugated N-hydroxyindole-based LDH-A inhibitor designed to exploit the sugar avidity expressed by cancer cells (the Warburg effect). Herein we describe a structural modulation of the sugar moiety of this class of inhibitors, with the insertion of α-D-mannose, β-D-gulose, or β-N-acetyl-D-glucosamine portions in their structures. Their stereospecific chemical synthesis, which involves a substrate-dependent stereospecific glycosylation step, and their biological activity in reducing lactate production and proliferation in cancer cells are reported. Interestingly, the α-D-mannose conjugate displayed the best properties in the cellular assays, demonstrating an efficient antiglycolytic and antiproliferative activity in cancer cells.