Romagnoli Romeo, Baraldi Pier Giovanni, Pavani Maria Giovanna, Tabrizi Mojgan Aghazadeh, Preti Delia, Fruttarolo Francesca, Piccagli Laura, Jung M Katherine, Hamel Ernest, Borgatti Monica, Gambari Roberto
Dipartimento di Scienze Farmaceutiche, Università di Ferrara, 44100 Ferrara, Italy, and SAIC-Frederick Inc., National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland 21702, USA.
J Med Chem. 2006 Jun 29;49(13):3906-15. doi: 10.1021/jm060355e.
A new series of compounds in which the 2-amino-5-chlorophenyl ring of phenstatin analogue 7 was replaced with a 2-amino-5-aryl thiophene was synthesized and evaluated for antiproliferative activity and for inhibition of tubulin polymerization and colchicine binding to tubulin. 2-Amino-3-(3',4',5'-trimethoxybenzoyl)-5-phenyl thiophene (9f) as well as the p-fluoro-, p-methyl-, and p-methoxyphenyl substituted analogues (9i, j, and l, respectively) displayed high antiproliferative activities with IC50 values from 2.5 to 6.5 nM against the L1210 and K562 cell lines. Compounds 9i and j were more active than combretastatin A-4 as inhibitors of tubulin polymerization. Molecular docking simulations to the colchicine site of tubulin were performed to determine the possible binding mode of 9i. The results obtained demonstrated that antiproliferative activity correlated well with the inhibition of tubulin polymerization and the lengthening of the G2/M phase of the cell cycle. Moreover, a good correlation was found between these inhibitory effects and the induction of apoptosis in cells treated with the compounds.
合成了一系列新的化合物，其中将吩他汀类似物7的2-氨基-5-氯苯基环替换为2-氨基-5-芳基噻吩，并对其抗增殖活性、抑制微管蛋白聚合以及秋水仙碱与微管蛋白结合的能力进行了评估。2-氨基-3-(3',4',5'-三甲氧基苯甲酰基)-5-苯基噻吩(9f)以及对氟、对甲基和对甲氧基苯基取代的类似物(分别为9i、j和l)对L1210和K562细胞系显示出高抗增殖活性，IC50值为2.5至6.5 nM。化合物9i和j作为微管蛋白聚合抑制剂比康普他汀A-4更具活性。进行了针对微管蛋白秋水仙碱结合位点的分子对接模拟，以确定9i可能的结合模式。所得结果表明，抗增殖活性与抑制微管蛋白聚合以及细胞周期G2/M期的延长密切相关。此外，在用这些化合物处理的细胞中，这些抑制作用与细胞凋亡的诱导之间发现了良好的相关性。
