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

Bispidine (3,7-diazabicyclo[3.3.1]­nonane, C<sub>7</sub>H<sub>14</sub>N<sub>2</sub>) analogues of cisplatin, carboplatin, and oxaliplatin have been prepared. (C<sub>7</sub>H<sub>14</sub>N<sub>2</sub>)­PtCl<sub>2</sub>·DMF (<b>1b</b>), obtained from (1,5-hexadiene)­PtCl<sub>2</sub> and bispidine in DMF, is dimeric in the solid state. Dissolving <b>1b</b> in hot <i>N</i>-methylformamide allows crystallization of the solvent-free polymeric (C<sub>7</sub>H<sub>14</sub>N<sub>2</sub>)­PtCl<sub>2</sub> (<b>1a</b>). Recrystallization of <b>1a</b>,<b>b</b> from hot water yields the trihydrate (C<sub>7</sub>H<sub>14</sub>N<sub>2</sub>)­PtCl<sub>2</sub>·3H<sub>2</sub>O (<b>1c</b>). Reaction of <b>1</b> with Ag<sub>2</sub>(cbdca) (cbdca = 1,1-cyclobutanedicarboxylate) in water affords the pentahydrate (C<sub>7</sub>H<sub>14</sub>N<sub>2</sub>)­Pt­{C<sub>4</sub>H<sub>6</sub>(CO<sub>2</sub>)<sub>2</sub>}·5H<sub>2</sub>O (<b>2b</b>), which loses water in vacuo to give (C<sub>7</sub>H<sub>14</sub>N<sub>2</sub>)­Pt­{C<sub>4</sub>H<sub>6</sub>(CO<sub>2</sub>)<sub>2</sub>} (<b>2a</b>). Reaction of <b>1</b> with AgNO<sub>3</sub> in water, followed by addition of Na<sub>2</sub>C<sub>2</sub>O<sub>4</sub>, affords the water-free polymeric (C<sub>7</sub>H<sub>14</sub>N<sub>2</sub>)­Pt­(C<sub>2</sub>O<sub>4</sub>) (<b>3</b>). All complexes have been structurally characterized, revealing various patterns of N–H···Cl and N–H···O hydrogen bonds. In the hydrates <b>1c</b> and <b>2b</b> the complexes are embedded in intricate three-dimensional water networks. Complexes <b>1a</b>, <b>2a</b>, and <b>3</b> 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.