A class of novel tubulin polymerization inhibitors exert effective anti-tumor activity via mitotic catastrophe

In current work, a class of novel 4,5-dihydro-1H-pyrazole-1-carboxylate derivatives (E01-E28) were designed, synthesized and evaluated. Among them, the most potent compound E24 exhibited comparable activity against a panel of cancer cells (GI(50) ranging 0.05-0.98 mu M) and tubulin polymerization inhibition (IC50 = 1.49 mu M) with reference drug CA-4(P) (GI(50) ranging 0.019-0.32 mu M, IC50 = 2.18 mu M). The following assays indicated that compound E24 disturbed the dynamics of tubulin catastrophe and rescue, which triggered G2/M arrest, leading to ROS accumulation, cleavage of PARP and apoptosis. Molecular dynamics simulation validated that compound E24 could tightly bind into tubulin heterodimers with beta Lys 254 and beta Cys 241 of tubulin in the docking pose. Metabolic stability and pharmacokinetics parameters were also determined. The half time (t(1/2)) displayed species differences in three microsomes. The plasma elimination half-life (t(1/2)), peak plasma concentration (C-max), mean retention time (MRT), the area under the curve (AUC(0-infinity),) and distribution volume (V-z) of E24 after intravenous administration were 0.90 +/- 0.22 h, 594.50 +/- 97.23 ng/mL, 1.09 +/- 0.22 h, 413.67 +/- 105.64 ng/mL*h and 5.03 +/- 1.82 L/kg, respectively. In HeLa-xenografts, compound E24 exhibited obvious antitumor efficacy via the suppression of tumor growth without weight loss of body or organ. In brief, compound E24 might be a hopeful candidate with excellent properties for oncotherapy as tubulin polymerization inhibitor. (C) 2018 Elsevier Masson SAS. All rights reserved.