Design, synthesis and biological evaluation of benz‐fused five‐membered heterocyclic compounds as tubulin polymerization inhibitors with anticancer activities

Abstract

A series of benz‐fused five‐membered heterocyclic compounds were designed and synthesized as novel tubulin inhibitors targeting the colchicine binding site. Among them, compound 4d displayed the highest antiproliferative activity against four cancer cell lines with an IC50 value of 4.9 μM in B16‐F10 cells. Compound 4d effectively inhibited tubulin polymerization in vitro (IC50 of 13.1 μM). Further, 4d induced cell cycle arrest in G2/M phase. Finally, 4d inhibited the migration of cancer cells in a dose‐dependent manner. In summary, these results suggest that compound 4d represents a new class of tubulin inhibitors deserving further investigation.

Imidazole as a Promising Medicinal Scaffold: Current Status and Future Direction

“…These four compounds exhibited high bioactivity scores as kinase inhibitors that provide additional confirmation to the reported studies. 14 , 20 , 21 Moreover, compound C10 could act via four mechanisms one of which is GPCR which is consistent with the previously reported study about C10 and its action through dimerization of estrogen receptor. 18 Compound C11 was suggested to stabilize DNA c-MYC G-quadruplex by modulating ion-channel and this was confirmed with our target prediction score of 0.30.…”

“…The result suggested that C8 has a dose-dependent effect in inhibiting tubulin polymerization and suppressing the cell cycle in the G2/M phase. 21 …”

“… Activation of p38 signaling pathway. [ 16 ] Human umbilical vein endothelial cells (HUVECs) 0.4 Smooth muscle cells (SMCs) 5.5 IC 50 (µM) Exhibited excellent inhibitory activity on tumor growth in vivo [ 17 ] Human myeloid leukemia cells (HL-60) 0.2 Human myeloid leukemia cells (K562) 1 Human myeloid leukemia cells (K562R) (multidrug-resistant cells) 0.9 Human prostate carcinoma cells (PC-3) 3.1 Human breast carcinoma cells (MCF-7) 10.6 Human esophageal carcinoma cells (ECA-109) 3.8 Human hepatocarcinoma cells (BEL-7402) 1.2 Human non-small lung cancer cells (A549) 1.3 IC 50 (µM) Inhibit tubulin polymerization and arrest cell cycle at G2/M phase [ 21 ] MCF-7 9.450±0.292 H1299 7.652±0.215 HeLa 6.862±0.144 B16-F10 4.912±0.088 HUVEC >50 IC 50 (µM) Arrest cell cycle at G1 phase and induce apoptosis [ 22 ] HeLa 82.83±1.37 …”

“…The result suggested that C8 has a dose-dependent effect in inhibiting tubulin polymerization and suppressing the cell cycle in the G2/M phase. 21 On investigating the cytotoxicity of imidazole compounds against cervical cancer, it was reported that C9 possesses a potent anticancer activity with IC 50 of 0.08 µM, which was comparable to 5-fluorouracil with IC 50 0.09 µM. The potential mechanism of C9 was via suppressing the cell cycle at the G1 phase and inducing apoptosis.…”

Recent Advances in the Synthesis of Fused Heterocyclic Compounds and Their Antitumor Activities

“…Keywords unsaturated hydrocarbons; transition metal-catalysis; fused heterocyclic compounds; antitumor activity 稠杂环化合物是指苯环与杂环或杂环与杂环稠合 在一起的化合物(如吲哚、喹啉、嘌呤等 [1][2][3] ). 由于稠杂 环化合物通常具有独特的生物活性、低毒性和高内吸收 性 [4][5][6][7] , 经常用作医药活性分子和农药的结构单元 [8][9][10][11] . 到目前为止, 全球销售额前 200 的药物中许多化合物含 有稠杂环结构(图 1).…”