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 platin um complexes with linear coordinating spermidine and spermine is repor ted. The synthetic pathway involves first the three-step selective pro tection of the polyamines, giving bis(trifluoroacetyl)polyamines (1, 4 ), (tert-butoxycarbonyl)bis(trifluoroacetyl) (2, 5), and (tert-butoxyc arbonyl)polyamines (3, 6), respectively. The platination at desired si tes with activated species of cis-or trans-[PtCl2(NH3)(2)] (CDDP or TD DP,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 n ot isolated). Through final deprotection, three different complexes we re obtained and further investigated: trans-PtCl(NH3)(2)}(2){mu-spermi dine-N-1,N-8}]Cl-3 (8), [{trans-PtCl(NH3)(2)}(2)- {mu-spermine-N-1,N-1 2}]Cl-4 (10), and [{cis-PtCl(NH3)(2)}(2){mu-spermine-N-1,N-12}]Cl-4 (1 1). One-and two-dimensional NMR solution studies provided evidence tha t 11, at physiological pH, forms an inert bis((tetraamine)platinum) sp ecies in which each Pt is chelated by a central and a terminal amino g roup. In contrast, complexes 8 and 10 retain their reactivity, showing only reversible formation of hydroxo bridges. The comparison of in vi tro cytotoxicity data for 8, 10, and 11 with data for previously descr ibed bifunctional dinuclear complexes shows the enhanced activity part icularly of complex 8 in the CDDP-resistant L1210 cell line. The bindi ng of 8 and 10 to poly(dG-dC).poly(dG-dC) is further increased and als o reflected by B --> Z conformational changes at lower doses.