Dibutyltin(IV) complexes containing arylazobenzoate ligands: chemistry, in vitro cytotoxic effects on human tumor cell lines and mode of interaction with some enzymes

Invest New Drugs. 2011 Apr;29(2):285-99. doi: 10.1007/s10637-009-9360-3. Epub 2009 Dec 11.

Abstract

Dibutyltin(IV) complexes of composition Bu₂Sn(LH)₂, where LH is a carboxylate residue derived from 2-[(E)-(5-tert-butyl-2-hydroxyphenyl)diazenyl]benzoate (L¹H) with water molecule (1), 4-[(E)-(5-tert-butyl-2-hydroxyphenyl)diazenyl]benzoate (L²H) (2) and 4-[(E)-(4-hydroxy-5-methylphenyl)diazenyl]benzoate (L³H) (3), were synthesized and characterized by spectroscopic (¹H, ¹³C and ¹¹⁹Sn NMR, IR, ¹¹⁹Sn Mössbauer) techniques. A full characterization was accomplished from the crystal structure of complex 1. The molecular structures and geometries of the complexes (1a i.e. 1 without water molecule and 3) were fully optimized using the quantum mechanical method (PM6). Complexes 1 and 3 were found to exhibit stronger cytotoxic activity in vitro across a panel of human tumor cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. Compound 3 is found to be four times superior for the A498, EVSA-T and MCF-7 cell lines than CCDP (cisplatin), and four, eight and sixteen times superior for the A498, H226 and MCF-7 cell lines, respectively, compared to ETO (etoposide). The mechanistic role of cytotoxic activity of test compounds is discussed in relation to the theoretical results of docking studies with some key enzymes such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II associated with the propagation of cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • DNA Topoisomerases, Type II / chemistry
  • DNA Topoisomerases, Type II / metabolism
  • Drug Screening Assays, Antitumor
  • Enzymes / metabolism*
  • Humans
  • Hydrogen Bonding / drug effects
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Organotin Compounds / chemistry*
  • Organotin Compounds / metabolism
  • Organotin Compounds / pharmacology*
  • Quantum Theory
  • Ribonucleotide Reductases / chemistry
  • Ribonucleotide Reductases / metabolism
  • Thymidylate Synthase / chemistry
  • Thymidylate Synthase / metabolism

Substances

  • Enzymes
  • Ligands
  • Organotin Compounds
  • di-n-butyltin
  • Ribonucleotide Reductases
  • Thymidylate Synthase
  • DNA Topoisomerases, Type II