Selective platination of biologically relevant polyamines. Linear coordinating spermidine and spermine as amplifying linkers in dinuclear platinum complexes

A new approach to the synthesis of novel bifunctional dinuclear platinum complexes with linear coordinating spermidine and spermine is reported. The synthetic pathway involves first the three-step selective protection of the polyamines, giving bis(trifluoroacetyl)polyamines (1, 4), (tert-butoxycarbonyl)bis(trifluoroacetyl) (2, 5), and (tert-butoxycarbonyl)polyamines (3, 6), respectively. The platination at desired sites with activated species of cis-or trans-[PtCl2(NH3)(2)] (CDDP or TDDP,respectively) produces the BOG-protected dinuclear species [{cis-or trans-PtCl(NH3)2)(2)}(2)(mu-L)]X (7, L = BOC-spermidine, X = (NO3)(0.75)Cl-1.25; 9, L = (BOC)(2)-spermine, X = Cl-2; cis spermine species not isolated). Through final deprotection, three different complexes were obtained and further investigated: [{trans-PtCl(NH3)(2)}(2){mu-spermidine-N-1,N-8}]Cl-3 (8), [{trans-PtCl(NH3)(2)}(2)- {mu-spermine-N-1,N-12}]Cl-4 (10), and [{cis-PtCl(NH3)(2)}(2){mu-spermine-N-1,N-12}]Cl-4 (11). One-and two-dimensional NMR solution studies provided evidence that 11, at physiological pH, forms an inert bis((tetraamine)platinum) species in which each Pt is chelated by a central and a terminal amino group. In contrast, complexes 8 and 10 retain their reactivity, showing only reversible formation of hydroxo bridges. The comparison of in vitro cytotoxicity data for 8, 10, and 11 with data for previously described bifunctional dinuclear complexes shows the enhanced activity particularly of complex 8 in the CDDP-resistant L1210 cell line. The binding of 8 and 10 to poly(dG-dC).poly(dG-dC) is further increased and also reflected by B --> Z conformational changes at lower doses.