Synthesis and Biological Evaluations of Monocarbonyl Curcumin Inspired Pyrazole Analogues as Potential Anti-Colon Cancer Agent

Drug Des Devel Ther. 2020 Jun 29:14:2517-2534. doi: 10.2147/DDDT.S244865. eCollection 2020.

Abstract

Purpose: The monocarbonyl analogs of curcumin (MCACs) have been widely studied for their promising antitumor activity. Pyrazole is a five-membered aromatic heterocyclic system with various bioactivities incorporated frequently in drugs. However, few of MCACs inspired pyrazole analogues were investigated. To search for more potent cytotoxic agents based on MCACs, a series of new 1,5-diaryl/heteroaryl-1,4-pentadien-3-ones inspired pyrazole moiety was synthesized and evaluated on their anti-colon cancer activities.

Methods: Fifteen new compounds were synthesized and characterized by spectral datum, and then they were tested preliminarily by MTT assay for their cytotoxic activities against a panel of four human cancer cell lines, namely, gastric (SGC-7901), liver (HepG2), lung (A549), and colon (SW620) cancer cells. Compound 7h exhibited excellent selectivity and outstanding anti-proliferation activity against SW620 cells among these 15 compounds. Further, the mechanisms were investigated by transwell migration and invasion assay, clonogenic assay, cell apoptosis analysis, cell cycle analysis, Western blot analysis.

Results: The IC50 value of 7h against SW620 cells was 12 nM, being more potent than curcumin (IC50 = 9.36 μM), adriamysin (IC50 = 3.28 μM) and oxaliplatin (IC50 = 13.33 μM). Further assays showed that 7h inhibited SW620 cell migration, invasion and colony formation obviously, which was due to its ability to induce cell cycle arrest in the G2/M and S phases and apoptosis. Western blot assay revealed that 7h decreased the protein expression of ATM gene, which may primarily contribute to its anticancer activity against SW620 cells.

Conclusion: A new MCACs 7h was synthesized and found to exhibit excellent anti-proliferation activity against SW620 cells. Further studies indicated that 7h exerted its anticancer activity against SW620 cells probably via decreasing the ATM protein expression. The present study suggested that 7h was a promising candidate as an anti-colon cancer drug for future development.

Keywords: 1, 5-diheteroarylpenta-1, 4-dien-3-one; ATM gene; cell apoptosis; cell proliferation; colon cancer.

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemical synthesis
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cells, Cultured
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Colonic Neoplasms / pathology
  • Curcumin / chemical synthesis
  • Curcumin / chemistry
  • Curcumin / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antineoplastic Agents, Phytogenic
  • Pyrazoles
  • pyrazole
  • Curcumin