Triphenyltin(IV) 2-[(E)-2-(aryl)-1-diazenyl]benzoates as anticancer drugs: synthesis, structural characterization, in vitro cytotoxicity and study of its influence towards the mechanistic role of some key enzymes

Invest New Drugs. 2010 Oct;28(5):587-99. doi: 10.1007/s10637-009-9293-x. Epub 2009 Jul 30.

Abstract

Triphenyltin(IV) complexes of composition [Ph(3)SnL(1)H](n) (1) and [Ph(3)SnL(2)H](n) (2) (where L(1)H = 2-[(E)-2-(3-formyl-4-hydroxyphenyl)-1-diazenyl]benzoate and L(2)H = 2-[(E)-2-(4-Hydroxy-5-methylphenyl)-1-diazenyl]benzoate) were synthesized and characterized by spectroscopic ((1)H, (13)C and (119)Sn NMR, IR, (119)Sn Mössbauer) techniques in combination with elemental analysis. The molecular structures and geometries of the complexes (1 and 2) were fully optimized using the quantum mechanical method (PM3). Complexes (1 and 2) were found to exhibit stronger cytotoxic activity in vitro across a panel of human tumour cell lines viz., A498, EVSA-T, H226, IGROV, M19 MEL, MCF-7 and WIDR. The test compounds 1 and 2 exhibit comparable results and both the compounds are found to be far superior to CCDP (cisplatin), 5-FU (5-fluorouracil) and ETO (etoposide) across a panel of cell lines and the activity is more pronounced for the A498 (22 fold) and H226 (33 fold) cell lines compared to CCDP, and A498 (13 fold), H226 (39 fold) and MCF-7 (33 fold) cell lines compared to ETO. The test compounds are even 23 fold more active in magnitude in terms of the ID(50) value at least against the H226 cell lines when compared with MTX (methotrexate). Further, the mechanistic role of cytotoxic activity of test compounds (1 and 2), are discussed in relations to the theoretical results of docking studies with some of the key enzymes such as ribonucleotide reductase, thymidylate synthase, thymidylate phosphorylase and topoisomerase II.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Binding Sites
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Organotin Compounds / chemical synthesis*
  • Organotin Compounds / chemistry
  • Organotin Compounds / pharmacology*
  • Quantum Theory
  • Ribonucleotide Reductases / chemistry
  • Ribonucleotide Reductases / metabolism*
  • Spectrophotometry, Infrared
  • Thermodynamics
  • Thymidylate Synthase / chemistry
  • Thymidylate Synthase / metabolism*

Substances

  • Antineoplastic Agents
  • Organotin Compounds
  • triphenyltin
  • Ribonucleotide Reductases
  • Thymidylate Synthase