Zubaș Andreea, Ghinet Alina, Farce Amaury, Dubois Joëlle, Bîcu Elena
Faculty of Chemistry, 'Alexandru Ioan Cuza' University of Iasi, Bulevardul Carol I, nr. 11, 700506 Iasi, Romania.
Junia, Health and Environment, Laboratory of Sustainable Chemistry and Health, 59000 Lille, France.
Pharmaceuticals (Basel). 2023 Jun 16;16(6):888. doi: 10.3390/ph16060888.
In the search for innovative approaches to cancer chemotherapy, a chemical library of 49 cyanochalcones, , , and , was designed as dual inhibitors of human farnesyltransferase (FTIs) and tubulin polymerization (MTIs) (FTIs/MTIs), two important biological targets in oncology. This approach is innovative since the same molecule would be able to interfere with two different mitotic events of the cancer cells and prevent these cells from developing an emergency route and becoming resistant to anticancer agents. Compounds were synthesized by the Claisen-Schmidt condensation of aldehydes with -3-oxo-propanenitriles under classical magnetic stirring and under sonication. Newly synthesized compounds were screened for their potential to inhibit human farnesyltransferase, tubulin polymerization, and cancer cell growth in vitro. This study allowed for the identification of 22 FTIs and 8 dual FTIs/MTIs inhibitors. The most effective molecule was carbazole-cyanochalcone , bearing a 4-dimethylaminophenyl group (IC (h-FTase) = 0.12 µM; IC (tubulin) = 0.24 µM) with better antitubulin activity than the known inhibitors that were previously reported, phenstatin and (-)-desoxypodophyllotoxin. The docking of the dual inhibitors was realized in both the active site of FTase and in the colchicine binding site of tubulin. Such compounds with a dual inhibitory profile are excellent clinical candidates for the treatment of human cancers and offer new research perspectives in the search for new anti-cancer drugs.
在寻找癌症化疗创新方法的过程中，设计了一个包含49种氰基查耳酮（、、和）的化学文库，作为人法尼基转移酶（FTIs）和微管蛋白聚合（MTIs）（FTIs/MTIs）的双重抑制剂，这是肿瘤学中的两个重要生物学靶点。这种方法具有创新性，因为同一分子能够干扰癌细胞的两种不同有丝分裂事件，并防止这些细胞形成应急途径并对抗癌药物产生耐药性。通过醛与-3-氧代丙腈在经典磁力搅拌和超声处理下的克莱森-施密特缩合反应合成化合物。对新合成的化合物进行体外抑制人法尼基转移酶、微管蛋白聚合和癌细胞生长潜力的筛选。该研究鉴定出22种FTIs和8种双重FTIs/MTIs抑制剂。最有效的分子是咔唑-氰基查耳酮，带有4-二甲基氨基苯基（IC（h-FTase）=0.12μM；IC（微管蛋白）=0.24μM），其抗微管蛋白活性优于先前报道的已知抑制剂苯抑素和（-）-脱氧鬼臼毒素。在FTase的活性位点和微管蛋白的秋水仙碱结合位点都实现了双重抑制剂的对接。这种具有双重抑制特性的化合物是治疗人类癌症的优秀临床候选药物，并为寻找新的抗癌药物提供了新的研究视角。
