Yushyn Ihor, Holota Serhii, Finiuk Nataliya, Senkiv Julia, Karpenko Olexandr, Vovchuk Orysya, Kozak Yuliia, Ivasechko Iryna, Pinyazhko Roman, Gzella Andrzej, Świątek Piotr, Stoika Rostyslav, Lesyk Roman
Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine; Molecular Design Center, Danylo Halytsky Lviv National Medical University, Pekarska 69, 79010 Lviv, Ukraine.
Molecular Design Center, Danylo Halytsky Lviv National Medical University, Pekarska 69, 79010 Lviv, Ukraine; Institute of Cell Biology of National Academy of Sciences of Ukraine, Drahomanov14/16, Lviv 79005, Ukraine.
Bioorg Med Chem. 2025 Oct 1;128:118291. doi: 10.1016/j.bmc.2025.118291. Epub 2025 Jun 22.
Molecular hybridization is a rational strategy for the design of new heterocyclic molecules with potential anticancer activity. Two series of linked and fused bioisosteric pyrazole-thiazole-bearing hybrid molecules were synthesized as promising anticancer agents. Synthetic approaches based on aminolysis and Knoevenagel condensation were used for the creation of target 5-ene-4-((5-methyl-1H-pyrazol-3-yl)amino)thiazol-2(5H)-ones 3a-d and their fused analogs - pyrazolo[3,4-b]thiazolo[5,4-e]pyridines 4a-f. The structure of these hybrids was confirmed by means of NMR/LC-MS spectra and X-ray analysis. Novel pyrazole-thiazole hybrid molecules were screened on "60 lines screening" (DTP NCI) and a panel of human cancer cell lines. The derivative 3b was identified as the most active molecule against leukemic cell line CCRF-CEM (GI = 1.01 μM), while the compound 3c demonstrated the highest toxicity towards human leukemia Jurkat T-cells (IC = 5.66 ± 0.61 μM) and induced apoptotic DNA fragmentation in these cells (40.90 ± 1.07 %). It was also highly toxic for MCF-7 breast adenocarcinoma cells (IC = 2.17 ± 0.36 μM). At the same time, the compound 3c exhibited low toxicity towards pseudo-normal cells of HaCaT (IC = 68.23 ± 0.54 μM), BALB/3T3 (IC = 56.03 ± 0.54 μM), and Mv1Lu (IC = 50.05 ± 0.44 μM) lines. A significant difference in the anticancer activity in vitro was detected between synthesized derivatives and linked hybrids which showed higher activity compared to fused analogs. Pharmacokinetic analysis of the developed molecules 3a-c predicts their potential as promising anticancer agents with further need in investigation of the mechanisms of their action.
分子杂交是设计具有潜在抗癌活性的新型杂环分子的合理策略。合成了两个系列的含连接和稠合生物电子等排体吡唑 - 噻唑的杂化分子作为有前景的抗癌剂。基于氨解和Knoevenagel缩合的合成方法用于制备目标5-烯-4-((5-甲基-1H-吡唑-3-基)氨基)噻唑-2(5H)-酮3a - d及其稠合类似物 - 吡唑并[3,4 - b]噻唑并[5,4 - e]吡啶4a - f。这些杂化物的结构通过NMR/LC - MS光谱和X射线分析得到证实。新型吡唑 - 噻唑杂化分子在“60系筛选”(DTP NCI)和一组人类癌细胞系上进行了筛选。衍生物3b被鉴定为对白血病细胞系CCRF - CEM最具活性的分子(GI = 1.01 μM)，而化合物3c对人白血病Jurkat T细胞表现出最高毒性(IC = 5.66 ± 0.61 μM)并在这些细胞中诱导凋亡性DNA片段化(40.90 ± 1.07%)。它对MCF - 7乳腺腺癌细胞也具有高毒性(IC = 2.17 ± 0.36 μM)。同时，化合物3c对HaCaT、BALB/3T3和Mv1Lu系的假正常细胞表现出低毒性(IC分别为68.23 ± 0.54 μM、56.03 ± 0.54 μM和50.05 ± 0.44 μM)。在合成衍生物和连接的杂化物之间检测到体外抗癌活性的显著差异，连接的杂化物比稠合类似物表现出更高的活性。对所开发分子3a - c的药代动力学分析预测它们作为有前景的抗癌剂的潜力，进一步需要研究其作用机制。
