One of the recent targets is histone deacetylase (HDAC) which provide a very promising new approach for anticancer drugs, which may combine clinical efficacy with relatively mild toxicological side effects. Modification of histone acetylation level, promoted by histone acetylase (HAT) and HDAC enzyme, has been recognize to play an important role in epigenetic modulation of gene expression, so HDAC inhibitors are considered a new class of anticancer agents. A new series of hydroxamic and carboxylic acid analogues based on the 1,3,4-thiadiazole scaffold has been designed and synthesized with the aim of exploring its potential as new antitumor agents. Biological results have revealed that the structural modifications proposed significantly affected inhibitory potency as well as selectivity for HDAC inhibitors. Most target compounds are significantly more active, specifically 5a, 5b, 5e with IC₅₀ values in the low micromolar or, the most active compounds in the series. Selected compounds have been tested on the viability of MDA-MB-231 (breast cancer cell) and K562 (chronic myelogenous leukemia cell), A549 (human lung cancer), PC3 (Prostate cancer cell lines) using MTT assay. Docking simulations suggested that the most active compounds can recognize the binding site (PDB Code 1w22 reference compound) using a similar interactions network. These results have allowed us to rationalize the observed structure–activity relationships.

中文翻译：

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设计，合成，计算和生物学评估新型组氨酸十烷基化酶抑制剂异羟肟酸和羧酸衍生物

最近的目标之一是组蛋白脱乙酰基酶（HDAC），它为抗癌药物提供了非常有希望的新方法，可将临床疗效与相对温和的毒理学副作用相结合。由组蛋白乙酰化酶（HAT）和HDAC酶促进的组蛋白乙酰化水平的修饰已被认为在基因表达的表观遗传调制中起重要作用，因此HDAC抑制剂被认为是一类新的抗癌剂。设计并合成了基于1,3,4-噻二唑骨架的一系列新的异羟肟酸和羧酸类似物，旨在探索其作为新型抗肿瘤药的潜力。生物学结果表明，提出的结构修饰显着影响了HDAC抑制剂的抑制能力和选择性。如图5a，5b，5e所示，其IC ₅₀值处于低微摩尔浓度或系列中活性最高的化合物。使用MTT分析已对所选化合物的MDA-MB-231（乳腺癌细胞）和K562（慢性骨髓性白血病细胞），A549（人肺癌），PC3（前列腺癌细胞系）的生存力进行了测试。对接模拟表明，活性最高的化合物可以使用类似的相互作用网络识别结合位点（PDB代码1w22参考化合物）。这些结果使我们能够合理化观察到的结构-活性关系。