Bispidine analogues of cisplatin, carboplatin, and oxaliplatin. synthesis, structures, and cytotoxicity

Inorg Chem. 2014 Apr 7;53(7):3371-84. doi: 10.1021/ic402737f. Epub 2014 Mar 25.

Abstract

Bispidine (3,7-diazabicyclo[3.3.1]nonane, C7H14N2) analogues of cisplatin, carboplatin, and oxaliplatin have been prepared. (C7H14N2)PtCl2·DMF (1b), obtained from (1,5-hexadiene)PtCl2 and bispidine in DMF, is dimeric in the solid state. Dissolving 1b in hot N-methylformamide allows crystallization of the solvent-free polymeric (C7H14N2)PtCl2 (1a). Recrystallization of 1a,b from hot water yields the trihydrate (C7H14N2)PtCl2·3H2O (1c). Reaction of 1 with Ag2(cbdca) (cbdca = 1,1-cyclobutanedicarboxylate) in water affords the pentahydrate (C7H14N2)Pt{C4H6(CO2)2}·5H2O (2b), which loses water in vacuo to give (C7H14N2)Pt{C4H6(CO2)2} (2a). Reaction of 1 with AgNO3 in water, followed by addition of Na2C2O4, affords the water-free polymeric (C7H14N2)Pt(C2O4) (3). All complexes have been structurally characterized, revealing various patterns of N-H···Cl and N-H···O hydrogen bonds. In the hydrates 1c and 2b the complexes are embedded in intricate three-dimensional water networks. Complexes 1a, 2a, and 3 have been tested for their cytotoxicity against human cancer cell lines K562 (chronic myeloid leukemia), A2780 (ovarian cancer), and its platinum-resistant subline A2780 CisR and are compared to their parent analogues. The new complexes show significant cytotoxic activity along with a low platinum resistance factor.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / toxicity*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Carboplatin / analogs & derivatives*
  • Carboplatin / chemical synthesis
  • Carboplatin / toxicity*
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cisplatin / analogs & derivatives*
  • Cisplatin / chemical synthesis
  • Cisplatin / toxicity*
  • Coloring Agents
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Organoplatinum Compounds / chemical synthesis
  • Organoplatinum Compounds / toxicity*
  • Oxaliplatin
  • Structure-Activity Relationship
  • Tetrazolium Salts
  • Thiazoles

Substances

  • Antineoplastic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Coloring Agents
  • Organoplatinum Compounds
  • Tetrazolium Salts
  • Thiazoles
  • bispidine
  • Oxaliplatin
  • Carboplatin
  • thiazolyl blue
  • Cisplatin