| Abstract
| - A new approach to the synthesis of novel bifunctional dinuclearplatinum complexes with linear coordinatingspermidine and spermine is reported. The synthetic pathwayinvolves first the three-step selective protection ofthe polyamines, giving bis(trifluoroacetyl)polyamines(1, 4),(tert-butoxycarbonyl)bis(trifluoroacetyl)polyamines(2, 5), and(tert-butoxycarbonyl)polyamines (3,6), respectively. The platination at desired sites withactivatedspecies of cis- ortrans-[PtCl2(NH3)2](CDDP or TDDP, respectively) produces the BOC-protecteddinuclearspecies [{cis- ortrans-PtCl(NH3)2}2(μ-L)]X(7, L = BOC-spermidine, X =(NO3)0.75Cl1.25; 9,L = (BOC)2-spermine, X = Cl2; cis spermine species notisolated). Through final deprotection, three differentcomplexeswere obtained and further investigated: [{trans-PtCl(NH3)2}2{μ-spermidine-N1,N8}]Cl3(8),[{trans-PtCl(NH3)2}2{μ-spermine-N1,N12}]Cl4(10), and[{cis-PtCl(NH3)2}2{μ-spermine-N1,N12}]Cl4(11). One- and two-dimensionalNMR solution studies provided evidence that 11, atphysiological pH, forms an inertbis((tetraamine)platinum)species in which each Pt is chelated by a central and a terminal aminogroup. In contrast, complexes 8 and10retain their reactivity, showing only reversible formation of hydroxobridges. The comparison of in vitro cytotoxicitydata for 8, 10, and 11 with data forpreviously described bifunctional dinuclear complexes shows theenhancedactivity particularly of complex 8 in the CDDP-resistantL1210 cell line. The binding of 8 and 10 topoly(dG-dC)·poly(dG-dC) is further increased and also reflected by B→ Z conformational changes at lower doses.
- Novel bifunctionaldinuclear platinum complexes with linear spermidine and sperminecoordinating through the terminal primary amine groups have beensynthesized and characterized. The in vitro cytotoxicity andcircular dichroism studies show that these complexes have enhancedactivity in a cis-DDP resistant cell line and veryefficiently induce B → Z conformational changes inpoly(dG-dC)·poly(dG-dC).
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