Selective Platination of Biologically Relevant Polyamines. Linear Coordinating Spermidine and Spermine as Amplifying Linkers in Dinuclear Platinum Complexes

Abstract

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)polyamines (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 BOC-protected dinuclear species [{cis- or trans-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 not isolated). Through final deprotection, three different complexes were obtained and further investigated: [{trans-PtCl(NH3)2}2{μ-spermidine-N 1,N 8}]Cl3 (8), [{trans-PtCl(NH3)2}2{μ-spermine-N 1,N 12}]Cl4 (10), and [{cis-PtCl(NH3)2}2{μ-spermine-N 1,N 12}]Cl4 (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.

Synthesis of DNA‐Sequence‐Selective Hairpin Polyamide Platinum Complexes

“…These chemical shifts are consistent with similar metal complexes with PtN 3 Cl coordination spheres, where N = two trans-ammine ligands and one primary amine ligand. [16,17] Figure 1. 195 Pt NMR spectrum (top), 1 H NMR spectrum (middle) and ESI mass spectrum (bottom) of HLSP-6.…”

Amide-Based Prodrugs of Spermidine-Bridged Dinuclear Platinum. Synthesis, DNA Binding, and Biological Activity

“…BOC-protected spermidine and spermine complexes of this type are well-known as direct precursors in the synthesis of the free polyamine drugs 1,1/ t,t-spermidine and 1,1/t,t-spermine, respectively. 5 These blocked polyamine-bridged complexes are 2-3 orders of magnitude less cytotoxic than the unprotected analogues containing the protonated quaternary nitrogens. Release of the active species can be achieved through spontaneous, pH dependent hydrolysis of the blocking groups.…”

Spectroscopic and Theoretical Studies on Solid 1,2‐Ethylenediamine Dihydrochloride Salt

“…[6,15,17,18] In addition, it was verified that linkage of some of these molecules to previously tested anticancer drugs leads to a higher cytotoxic effect and, in some cases, even to an enhancement of the efficacy of the long-used first-generation drug cisplatin [cis-diamine dichloroplatinum(II)]. [19][20][21][22][23][24][25][26][27] Recently, it was also demonstrated that polyamines may exert insulinlike activity by interacting with receptors on fat-cell membranes. [28] Despite the vital role of polyamines in living cells, little is known about their structure at a molecular level.…”