Synthesis and Biological Evaluation of Novel Triazoles Linked 7-hydroxycoumarin as Potent Cytotoxic Agents

Anticancer Agents Med Chem. 2018;18(11):1531-1539. doi: 10.2174/1871520618666171229222956.

Abstract

Background: BacCancer is regarded as second leading cause of death worldwide. Therefore, there is a high demand for the discovery, development and improvement of novel anti-cancer agents which could efficiently prevent proliferative pathways and clonal expansion of cells.

Objective: In view of this, a new series of bioactive scaffolds viz triazoles linked 7-hydroxycoumarin (1) were synthesized using click chemistry approach.

Method: All the synthesized compounds were screened for cytotoxicity against a panel of seven different human cancer cell lines viz. Colon (Colo-205 and HCT-116), breast (MCF-7), lung (NCI-H322 and A549), prostate (PC-3) and skin (A-431) using 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) assay.

Results: Among all tested analogs, compound 5, displayed better cytotoxic activity as compared to the parent 7- hydroxycoumarin (1) with IC50 of 5.1, 22.7, 14.3 and 10.2 µM against breast (MCF-7), lung (NCI- H322), prostate (PC-3) and skin (A-431) cancer cell lines, respectively; the compound 5 was 8-fold more sensitive against MCF-7 than the parent 7-hydroxycoumarin. Moreover, Compound 5 induced both cytotoxic as well as cytostatic effects via induction of apoptosis and G1 phase arrest, respectively in breast cancer cells (MCF-7). The apoptotic cell population enhanced to 18.8% at 8 µM of 5 from 9.8% in case of negative control, while G1 phase arrest increased to 54.4% at 8 µM compared to negative control of 48.1%. Moreover, Compound 5 also exhibited a remarkable decrease in mitochondrial membrane potential (ΛΨm) leading to apoptosis of cancer cells used.

Conclusion: The structure-activity relationship study revealed that the derivatives bearing electron-withdrawing substituents were more effective. The present study resulted in identification of the compounds demonstrating broad spectrum cytotoxic activity.

Keywords: 7-hydroxycoumarin; Natural products; cancer cell lines; cytotoxic agents; prangos pabularia; structure modification..

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cytotoxins / chemical synthesis
  • Cytotoxins / chemistry
  • Cytotoxins / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Membrane Potential, Mitochondrial / drug effects
  • Molecular Structure
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*
  • Umbelliferones / chemistry
  • Umbelliferones / pharmacology*

Substances

  • Antineoplastic Agents
  • Cytotoxins
  • Triazoles
  • Umbelliferones
  • 7-hydroxycoumarin