1H-Benzimidazole-2-Yl 腙对微管蛋白聚合、细胞毒性和抗氧化活性的调节作用。,Molecules

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1H-Benzimidazole-2-Yl 腙对微管蛋白聚合、细胞毒性和抗氧化活性的调节作用。
Molecules ( IF 4.2 ) Pub Date : 2022-12-29 , DOI: 10.3390/molecules28010291
Maria Argirova ₁ , Maya Guncheva ₁ , Georgi Momekov ₂ , Emiliya Cherneva _{1,

2} , Rositsa Mihaylova ₂ , Miroslav Rangelov ₁ , Nadezhda Todorova ₃ , Petko Denev ₁ , Kameliya Anichina ₄ , Anelia Mavrova ₄ , Denitsa Yancheva ₁

Affiliation

设计了具有不同羟基和甲氧基苯基部分的 1H-苯并咪唑-2-基腙。它们对微管蛋白聚合的影响在体外对猪微管蛋白进行了评估。与诺考达唑相比，这些化合物延长了成核阶段并减慢了微管蛋白聚合。通过在秋水仙碱结合位点进行分子对接，探索了腙与微管蛋白的可能结合模式。针对人类恶性细胞系 MCF-7 和 AR-230，以及针对正常成纤维细胞 3T3 和 CCL-1 评估了抗癌活性。在两种筛选的体外肿瘤模型中，这些化合物在低微摩尔浓度下表现出显着的抗肿瘤活性。最活跃的是三甲氧基取代的衍生物 1i 和位置异构体 1j 和 1k，含有羟基和甲氧基取代基：他们在两种肿瘤细胞系中显示出与参考鬼臼毒素相似的 IC50，并伴有对恶性转化细胞的高选择性。这些化合物具有中等至高度的清除过氧自由基和某些衍生物的能力 - 1l 含有间羟基和对甲氧基，1b-e 具有二/三羟基苯基部分，表明 HORAC 值高或与众所周知的酚类化合物相当抗氧化剂。因此，具有羟基/甲氧基苯基片段的 1H-苯咪唑-2-基腙被认为是表现出有前途的抗氧化和抗肿瘤联合作用的新药物。这些化合物具有中等至高度的清除过氧自由基和某些衍生物的能力 - 1l 含有间羟基和对甲氧基，1b-e 具有二/三羟基苯基部分，表明 HORAC 值高或与众所周知的酚类化合物相当抗氧化剂。因此，具有羟基/甲氧基苯基片段的 1H-苯咪唑-2-基腙被认为是表现出有前途的抗氧化和抗肿瘤联合作用的新药物。这些化合物具有中等至高度的清除过氧自由基和某些衍生物的能力 - 1l 含有间羟基和对甲氧基，1b-e 具有二/三羟基苯基部分，表明 HORAC 值高或与众所周知的酚类化合物相当抗氧化剂。因此，具有羟基/甲氧基苯基片段的 1H-苯咪唑-2-基腙被认为是表现出有前途的抗氧化和抗肿瘤联合作用的新药物。

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Modulation Effect on Tubulin Polymerization, Cytotoxicity and Antioxidant Activity of 1H-Benzimidazole-2-Yl Hydrazones.

1H-benzimidazol-2-yl hydrazones with varying hydroxy and methoxy phenyl moieties were designed. Their effect on tubulin polymerization was evaluated in vitro on porcine tubulin. The compounds elongated the nucleation phase and slowed down the tubulin polymerization comparably to nocodazole. The possible binding modes of the hydrazones with tubulin were explored by molecular docking at the colchicine binding site. The anticancer activity was evaluated against human malignant cell lines MCF-7 and AR-230, as well as against normal fibroblast cells 3T3 and CCL-1. The compounds demonstrated a marked antineoplastic activity in low micromolar concentrations in both screened in vitro tumor models. The most active were the trimethoxy substituted derivative 1i and the positional isomers 1j and 1k, containing hydroxy and methoxy substituents: they showed IC50 similar to the reference podophyllotoxin in both tumor cell lines, accompanied with high selectivity towards the malignantly transformed cells. The compounds exerted moderate to high ability to scavenge peroxyl radicals and certain derivatives-1l containing metha-hydroxy and para-methoxy group, and 1b-e with di/trihydroxy phenyl moiety, revealed HORAC values high or comparable to those of well-known phenolic antioxidants. Thus the 1H-benisimidazol-2-yl hydrazones with hydroxy/methoxy phenyl fragments were recognized as new agents exhibiting promising combined antioxidant and antineoplastic action.

更新日期：2022-12-29

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