Effect of the diamine nonleaving group in platinum-acridinylthiourea conjugates on DNA damage and cytotoxicity

J Med Chem. 2007 May 3;50(9):2259-63. doi: 10.1021/jm0614376. Epub 2007 Apr 5.

Abstract

The following complexes of type [PtCl(R)(ACRAMTU)](NO3)2 (ACRAMTU = 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea)), derived from prototype 1 (with R = ethane-1,2-diamine), were synthesized: 2 (with R = (1R,2R)-1,2-diaminocyclohexane), 3 (with R = propane-1,3-diamine), 4 (with R = N1,N1,N2,N2-tetramethylethane-1,2-diamine), and 5 (with R = 2,2'-bipyridine). The DNA sequence specificity of the conjugates and their antiproliferative potential in HL-60 and H460 cells were investigated. Conjugate 3 showed the strongest non-cisplatin-type DNA damage in polymerase stop assays and superior cell kill efficacy in H460 lung cancer (IC50 = 70 nM).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acridines / chemical synthesis*
  • Acridines / pharmacology
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology
  • Base Sequence
  • Cell Line, Tumor
  • Cisplatin / pharmacology
  • DNA Damage*
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Sequence Data
  • Organoplatinum Compounds / chemical synthesis*
  • Organoplatinum Compounds / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiourea / analogs & derivatives*
  • Thiourea / chemical synthesis*
  • Thiourea / pharmacology

Substances

  • Acridines
  • Antineoplastic Agents
  • Organoplatinum Compounds
  • chloro(1-(2-(acridin-9-ylamino)ethyl)-1,3-dimethylthiourea)(propane-1,3-diamine)platinum(II)
  • Thiourea
  • Cisplatin