The aquation profiles of two novel dinuclear polyamine-linked, platinum-based antitumour complexes [{trans-PtCl(15NH3)2}2{μ-(15NH2(CH2)615NH2(CH2)615NH2)}]3+ (BBR3007, 1,1/t,t-6,6, 1) and [{trans-PtCl(15NH3)2}2{μ-(15NH2(CH2)615NH2(CH2)215NH2(CH2)615NH2)}]4+ (BBR3610, 1,1/t,t-6,2,6, 1′) have been probed using 2D [1H, 15N] HSQC NMR spectroscopy. Reported herein are the rate constants for the hydrolysis of 1 and 1′, as well as the acid dissociation constants of the coordinated aqua ligands in their aquated derivatives. The aquation and anation rate constants for the single step aquation model in 15 mM NaClO4 (pH 5.4) at 298 K are, for 1, k1 = 7.2 ± 0.1 ×10−5 s−1, k−1 = 0.096 ± 0.002 M−1 s−1 and, for 1′, k1 = 4.0 ± 0.2 × 10−5 s−1, k−1 = 1.4 ± 0.1 M−1 s−1. The effect of the linker backbone (Pt(tetra(m)mine vs. polyamine) was evaluated by comparison with previous data for the trinuclear complex [{trans-PtCl(NH3)2}2(μ-trans-Pt(NH3)2{NH2(CH2)6NH2}2)]4+ (1,0,1/t,t,tor BBR3464). The pK1 for 1,0,1/t,t,t(3.44) is closest to that of 1 (3.12), while the pronounced difference for 1′ (4.54), means that 1′ is the least aquated of the three complexes at equilibrium. pKa values of 5.92 were calculated for the aquated forms of both 1 and 1′, which are 0.3 pKunits higher than for either 1,0,1/t,t,t, or the dinuclear 1,1/t,t. The higher pKa values for both polyamine-linked compounds may be attributed to the formation of macrochelates between the central NH2 groups and the {PtN3O}coordination sphere of the aquated species.

The first observation of a polyamine-DNA interaction using 2D [(1)H, (15)N] HSQC NMR spectroscopy allows study of the role of the linker in polynuclear platinum-DNA interactions and a novel "anchoring" of the polyamine by Pt-DNA bond formation allows examination of the details of conformational B → Z transitions induced by the polyamine. The kinetics and mechanism of the stepwise formation of 5'-5' 1,4-GG interstrand cross-links (IXLs) by fully (15)N-labeled [{trans-PtCl((15)NH(3))(2)}(2){μ-((15)NH(2)(CH(2))(6)(15)NH(2)(CH(2))(6)(15)NH(2))}](3+) (1,1/t,t-6,6, 1) and [{trans-PtCl((15)NH(3))(2)}(2){μ-((15)NH(2)(CH(2))(6)(15)NH(2)(CH(2))(2)(15)NH(2)(CH(2))(6)(15)NH(2))}](4+) (1,1/t,t-6,2,6, 1') with the self-complementary oligonucleotide 5'-{d(ATATGTACATAT)(2)} (duplex I) are compared to the analogous reaction with 1,0,1/t,t,t (BBR3464) under identical conditions (pH 5.4, 298 K). Initial electrostatic interactions with the DNA are delocalized and followed by aquation to form the monoaqua monochloro species. The rate constant for monofunctional adduct formation, k(MF), for 1 (0.87 M(-1) s(-1)) is 3.5 fold higher than for 1,0,1/t,t,t (0.25 M(-1) s(-1); the value could not be calculated for 1' due to peak overlap). The evidence suggests that several conformers of the bifunctional adduct form, whereas for 1,0,1/t,t,t only two discrete conformers were observed. The combined effect of the conformers observed for 1 and 1' may play a crucial role in the increased potency of these novel complexes compared to 1,0,1/t,t,t. Treated as a single final product, the rate of formation of the 5'-5' 1,4-GG IXL, k(CH), for 1 (k(CH) = 4.37 × 10(-5) s(-1)) is similar to that of 1,0,1/t,t,t, whereas the value for 1' is marginally higher (k(CH) = 5.4 × 10(-5) s(-1)).

Gamma9delta2T cells represent the most abundant population of human blood gammadeltaT lymphocytes. They produce and promote strong cytotoxic activity against many pathogens that are implicated in several human infectious diseases. Their activation requires their exposure to small phosphorus-containing antigens in the family of prenyl pyrophosphates and their related biosynthetic precursors such as isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are naturally occurring metabolites in mycobacteria and several other microbial pathogens. The broad specificity in the recognition of these molecules by the T-lymphocyte population expressing a Vgamma9Vdelta2 cell receptor might facilitate their manipulation by designing small potent synthetic agonist ligands. In this paper, we describe the synthesis and the biological evaluation of new pyrophosphonate compounds as new isosteric analogues of natural prenyl pyrophosphates. Several prenyl and alkenyl pyrophosphonate with different chain lengths and degrees of insaturation (24-28, 48-50, and 64-66) were tested as well as the alkoxymethylpyrophosphonic analogue of IPP (compound 76) as its closest isostere. Several of them appeared to be better activators of Vgamma9Vdelta2 T cell proliferation than IPP. These results open the perspective of a potential use of isoprenoides pyrophosphonates as specific immunoregulatory molecules.