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Discovery of New Antiproliferative Imidazopyrazole Acylhydrazones Able To Interact with Microtubule Systems.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-03-31 , DOI: 10.1002/cmdc.202000122
Chiara Brullo 1 , Federica Rapetti 1 , Silvana Alfei 2 , Irena Maric 3 , Francesca Rizzelli 4 , Marina Mapelli 4 , Camillo Rosano 5 , Maurizio Viale 6 , Olga Bruno 1
ChemMedChem ( IF 3.6 ) Pub Date : 2020-03-31 , DOI: 10.1002/cmdc.202000122
Chiara Brullo 1 , Federica Rapetti 1 , Silvana Alfei 2 , Irena Maric 3 , Francesca Rizzelli 4 , Marina Mapelli 4 , Camillo Rosano 5 , Maurizio Viale 6 , Olga Bruno 1
Affiliation
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Even though immunotherapy has radically changed the search for anticancer therapies, there are still many different pathways that are open to intervention with traditional small molecules. To expand our investigation in the anticancer field, we report here a new series of compounds in which our previous pyrazole and imidazopyrazole scaffolds are linked to a differently decorated phenyl ring through an acylhydrazone linker. Preliminary tests on the library were performed at the National Cancer Institute (USA) against the full NCI 60 cell panel. The best compounds among the imidazopyrazole series were then tested by immunofluorescence staining for their inhibition of cell proliferation, apoptosis induction, and their effect on the cell cycle and on microtubules. Two compounds, in particular 4‐benzyloxy‐3‐methoxybenzyliden imidazopyrazole‐7‐carbohydrazide showed good growth inhibition, with IC50 values in the low‐micromolar range, and induced apoptosis. Both compounds altered the cell‐cycle phases with the appearance of polyploid cells. Immunofluorescence analysis evidenced microtubules alterations; tubulin polymerization assays and docking studies suggested the tubulin system to be the possible, although not exclusive, target of the new acylhydrazone series reported here.
中文翻译：
发现了能够与微管系统相互作用的新型抗增殖咪唑并吡唑酰基。
即使免疫疗法从根本上改变了对抗癌疗法的寻求，但仍有许多不同的途径可供传统小分子干预。为了扩大我们在抗癌领域的研究，我们在此报告了一系列新化合物，其中我们以前的吡唑和咪唑并吡唑支架通过酰基hydr连接基连接到装饰不同的苯环上。在库中的初步测试是在美国国家癌症研究所针对完整的NCI 60细胞面板进行的。然后通过免疫荧光染色测试了咪唑并吡唑系列中最好的化合物对细胞增殖，凋亡诱导的抑制作用及其对细胞周期和微管的影响。两种化合物低微摩尔范围内有50个值，并诱导凋亡。两种化合物都随着多倍体细胞的出现改变了细胞周期阶段。免疫荧光分析表明微管发生改变；微管蛋白聚合分析和对接研究表明，微管蛋白系统可能是此处报道的新酰基hydr系列的靶标，尽管并非唯一。
更新日期：2020-03-31
中文翻译：
发现了能够与微管系统相互作用的新型抗增殖咪唑并吡唑酰基。
即使免疫疗法从根本上改变了对抗癌疗法的寻求，但仍有许多不同的途径可供传统小分子干预。为了扩大我们在抗癌领域的研究，我们在此报告了一系列新化合物，其中我们以前的吡唑和咪唑并吡唑支架通过酰基hydr连接基连接到装饰不同的苯环上。在库中的初步测试是在美国国家癌症研究所针对完整的NCI 60细胞面板进行的。然后通过免疫荧光染色测试了咪唑并吡唑系列中最好的化合物对细胞增殖，凋亡诱导的抑制作用及其对细胞周期和微管的影响。两种化合物低微摩尔范围内有50个值，并诱导凋亡。两种化合物都随着多倍体细胞的出现改变了细胞周期阶段。免疫荧光分析表明微管发生改变；微管蛋白聚合分析和对接研究表明，微管蛋白系统可能是此处报道的新酰基hydr系列的靶标，尽管并非唯一。
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