Design, synthesis, and <i>in silico</i> studies of pyrazolyl-thiazole and thiazolidinone hybrids as potential antiproliferative agents

Breast and liver cancers are the most common causes of cancer death and finding new anticancer agents is critical. Inspired by their antitumor potential, thiazole and thiazolidinone derivatives bearing a pyrazole core were prepared from thiosemicarbazone unit through reactions with carbon electrophiles. Compared to doxorubicin and roscovitine, <i>in vitro</i>, antiproliferative activity against MCF7 and HepG2 cancer cell panels implied the most potency of 2,4-dihydroxybenzylidene- and 4-dimethylaminobenzylidene-thiazolidinone, being capable of powerful interactions with protein receptors. In density functional theory simulation, the dimethylaminobenzylidine-thiazolidine exhibited the lowest energy gap and highest softness values. Consistently, the superlative docking score toward CDK2 protein (PDB ID: 2A4L) was shown by later compound through hydrogen bonding, arene-hydrogen, and arene-cation interactions with key nucleobases and amino acids of CDK2 protein which might be potential CDK2 inhibitor. According to ADME study, these compounds showed good lipophilicity and oral bioavailability. This work may contribute to the advancing of new potent antiproliferative agents.乳腺癌与肝癌是最常见的癌症致死病因，研发新型抗癌药物至关重要。鉴于其抗肿瘤潜力，研究团队以氨基硫脲（thiosemicarbazone）单元为原料，通过与亲电碳试剂反应，制备得到带有吡唑（pyrazole）母核的噻唑（thiazole）与噻唑烷二酮（thiazolidinone）衍生物。与多柔比星（doxorubicin）、罗司他丁（roscovitine）相比，体外（in vitro）实验中，针对MCF7与HepG2癌细胞株的抗增殖活性测试显示，2,4-二羟基亚苄基与4-二甲胺基亚苄基噻唑烷二酮的活性最强，可与蛋白受体发生强效相互作用。在密度泛函理论（density functional theory）模拟中，二甲胺基亚苄基噻唑烷展现出最低的能带隙与最高的柔软度数值。与之相符的是，该化合物对细胞周期蛋白依赖性激酶2（CDK2，PDB ID: 2A4L）展现出最优的对接评分，可通过与CDK2蛋白的关键核碱基及氨基酸残基形成氢键、芳环-氢以及芳环-阳离子相互作用，或为潜在的CDK2抑制剂。经ADME（吸收、分布、代谢、排泄）研究分析，此类化合物展现出良好的亲脂性与口服生物利用度。本研究可为新型强效抗增殖药物的研发提供助力。