Bispidine Analogues of Cisplatin, Carboplatin, and Oxaliplatin. Synthesis, Structures, and Cytotoxicity

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.