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Design, synthesis and biological evaluation of novel vicinal diaryl-substituted 1H-Pyrazole analogues of combretastatin A-4 as highly potent tubulin polymerization inhibitors.

Abstract
A series of 3-(3',4',5'-trimethoxyphenyl)-4-substituted 1H-pyrazole and their related 3-aryl-4-(3',4',5'-trimethoxyphenyl)-1-H-pyrazole regioisomeric derivatives, prepared as cis-rigidified combretastatin A-4 (CA-4) analogues, were synthesized and evaluated for their in vitro antiproliferative against six different cancer cell lines and, for selected highly active compounds, inhibitory effects on tubulin polymerization, cell cycle effects and in vivo potency. We retained the 3',4',5'-trimethoxyphenyl moiety as ring A throughout the present investigation, and a structure-activity relationship (SAR) information was obtained by adding electron-withdrawing (OCF3, CF3) or electron-releasing (alkyl and alkoxy) groups on the second aryl ring, corresponding to the B-ring of CA-4, either at the 3- or 4-position of the pyrazole nucleus. In addition, the B-ring was replaced with a benzo[b]thien-2-yl moiety. For many of the compounds, their activity was greater than, or comparable with, that of CA-4. Maximal activity was observed with the two regioisomeric derivatives characterized by the presence of a 4-ethoxyphenyl and a 3',4',5'-trimethoxyphenyl group at the C-3 and C-4 positions, and vice versa, of the 1H-pyrazole ring. The data showed that the 3',4',5'-trimethoxyphenyl moiety can be moved from the 3- to the 4-position of the 1H-pyrazole ring without significantly affecting antiproliferative activity. The most active derivatives bound to the colchicine site of tubulin and inhibited tubulin polymerization at submicromolar concentrations. In vivo experiments, on an orthotopic murine mammary tumor, revealed that 4c inhibited tumor growth even at low concentrations (5 mg/kg) compared to CA-4P (30 mg/kg).
AuthorsRomeo Romagnoli, Paola Oliva, Maria Kimatrai Salvador, Maria Encarnacion Camacho, Chiara Padroni, Andrea Brancale, Salvatore Ferla, Ernest Hamel, Roberto Ronca, Elisabetta Grillo, Roberta Bortolozzi, Fatlum Rruga, Elena Mariotto, Giampietro Viola
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 181 Pg. 111577 (Nov 01 2019) ISSN: 1768-3254 [Electronic] France
PMID31400707 (Publication Type: Journal Article)
CopyrightCopyright © 2019 The Authors. Published by Elsevier Masson SAS.. All rights reserved.
Chemical References
  • Antineoplastic Agents
  • Bibenzyls
  • Pyrazoles
  • Tubulin
  • Tubulin Modulators
  • combretastatin
Topics
  • Animals
  • Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
  • Bibenzyls (chemical synthesis, chemistry, pharmacology)
  • Cell Line, Tumor
  • Drug Design
  • Humans
  • Mice
  • Models, Molecular
  • Pyrazoles (chemical synthesis, chemistry, pharmacology)
  • Tubulin (metabolism)
  • Tubulin Modulators (chemical synthesis, chemistry, pharmacology)

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