New synthetic route to [bis-1,2-(aminomethyl)benzene]dichloroplatinum(II) complexes, screening for cytotoxic activity in cisplatin-sensitive and resistant human cancer cell lines, and reaction with glutathione

A new synthetic route to [bis-1,2-(aminomethyl)benzene]dichloroplatinum(II) complexes is described. o-Xylene and the 4-methoxy substituted derivative were used as starting points for the synthesis: benzylic bromination with N -bromosuccinamide/benzoylperoxide followed by the substitution of the benzy l bromides for azide and finally a catalytic hydrogenation with Pd/C of the diazides gave the desired diamines ligands. An attempt to synthesize the 4 ,6-dimethoxy derivative was unsuccessful due to the bromination of the arom atic ring. The diamines were complexed with K2PtCl4 to give the target Pt(I I) complexes: [1,2-bis(aminomethyl)benzene]dichloroplatinum(II) (4a) and [1 ,2-bis(aminomethyl)-4-methoxybenzene] dichloroplatinum(I 1) (4b). Screening for cytotoxic activity was done in comparison to cisplatin in a panel of e ight human cancer cell lines; in all cases, the 4-methoxy derivative 4b was less active than the unsubstituted analog, 4a. in four cell lines 4a was a s potent as cisplatin, while in the other four lines cisplatin was consider ably more potent then 4a. The 5637 bladder cancer cell line was made 4-5 fo ld resistant to either cisplatin or [d, l-trans-1,2-diaminocyclohexane]dich loroplatinum(II); 4a showed some cross resistance (2-3 fold) to both resist ant cell lines. The reactivity of 4a towards substitutions with glutathione (GSH), a biological thiol involved in intrinsic and acquired resistance to Pt-complexes, was measured by a RP-HPLC method. It was found that the seco nd-order rate constant for the reaction of 4a with GSH was similar to that that reported for CDDP, indicating that reactivity towards GSH does not exp lain the different levels of cross resistance.