DNA intercalators based on (1,10-phenanthrolin-2-yl)isoxazolidin-5-yl core with better growth inhibition and selectivity than cisplatin upon head and neck squamous cells carcinoma

Eur J Med Chem. 2018 Jan 1:143:583-590. doi: 10.1016/j.ejmech.2017.11.067. Epub 2017 Nov 26.

Abstract

((3RS,5SR)- and ((3RS,5RS)-2-(2-methoxybenzyl)-3-(1,10-phenanthrolin-2-yl)isoxazolidin-5-yl)methanol have been synthesized, according to 1,3-dipolar cycloaddition methodology, as DNA intercalating agents and evaluated for their anticancer activity against human cervical carcinoma HeLa and head and neck squamous cells carcinoma cell lines. The synthesized compounds exhibited good cytotoxic activity with IC50 better than cisplatin, used as the main and effective treatment for HNSCC, and a 24.3-72.0-fold selectivity respect to the 184B5 non-cancerous immortalized breast epithelial cell lines. Unwinding assay, circular dichroism data, and Uv-vis melting experiments confirmed that these compounds act as DNA intercalators with a binding constant in the order of 104 M-1. Docking studies showed that both compounds can interact as intercalating agent with both poly-d(AT)2 and poly-d(GC)2, preferring an entrance by the minor groove of the poly-d(AT)2.

Keywords: 1,3-Dipolar cycloaddition; DNA-intercalators; HeLa; Head and neck squamous cells carcinoma; Isoxazolidines.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Cisplatin / chemistry
  • Cisplatin / pharmacology*
  • DNA, Neoplasm / chemistry
  • DNA, Neoplasm / drug effects*
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / pathology
  • Humans
  • Intercalating Agents / chemical synthesis
  • Intercalating Agents / chemistry
  • Intercalating Agents / pharmacology*
  • Isoxazoles / chemical synthesis
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • Squamous Cell Carcinoma of Head and Neck
  • Structure-Activity Relationship

Substances

  • 2-(2-methoxybenzyl)-3-(1,10-phenanthrolin-2-yl)isoxazolidin-5-yl)methanol
  • Antineoplastic Agents
  • DNA, Neoplasm
  • Intercalating Agents
  • Isoxazoles
  • Cisplatin