Solution studies of dinuclear polyamine-linked platinum-based antitumour complexes

Abstract

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.

Ligand modulation of a dinuclear platinum compound leads to mechanistic differences in cell cycle progression and arrest

“…BBR3610 and BBR3610-DACH were synthesized as discussed earlier [12,15]. The stock solutions of platinum compounds were prepared at the concentration of 1 mM in water, stored at −20°C and diluted in complete medium.…”

“…1B), which was developed by replacing the central platinum with a spermine-like linker, is one of the most cytotoxic platinum compounds, with nanomolar toxicity in gliomas and colon cancer cells [10,11]. However, like its predecessor, BBR3610 was also found to undergo serum biotransformation leading to its degradation[12,13]. This was attributed to the substitution of the Pt-Cl bond by thiol compounds, resulting in bridge cleavage.…”

Design, synthesis and in vitro cytotoxicity of novel dinuclear platinum(II) complexes with a tetradentate carrier ligand

“…Polynuclear platinum(II) complexes represent a novel class of antitumor metallodrugs, in which two or three platinum centers are bridged by polyamines of variable length. These complexes bind to DNA by forming various long‐range intra‐strand and inter‐strand crosslinks . This unique DNA‐binding feature is believed to be responsible for distortion of the DNA conformation, enhanced cytotoxicity and effective prevention of resistance to the antitumor drugs .…”

“…These complexes bind to DNA by forming various long-range intra-strand and inter-strand crosslinks. [11][12][13] This unique DNA-binding feature is believed to be responsible for distortion of the DNA conformation, enhanced cytotoxicity and effective prevention of resistance to the antitumor drugs. [14][15][16] A major breakthrough in antitumor activity of polynuclear platinum complexes is reflected in the development of a trinuclear platinum(II) complex, BBR3464 ( Fig.…”

“…HT, which contains two DACH moieties, could afford four coordination sites to Pt 2+ and lay the foundation for the preparation of a series of novel dinuclear platinum complexes. Four dinuclear platinum complexes (H1-H4) with HT as carrier ligand and (COO À ) 2 , CH 2 (COO À ) 2 , CH 2 (CH 2 ) 2 C (COO À ) 2 and CH(OH)(CH 2 ) 2 C(COO À ) 2 as leaving groups were designed, synthesized and spectrally characterized using IR, 1 H NMR, 13 C NMR and MS spectroscopies. Their in vitro cytotoxicity against HepG-2, A549, HCT-116 and MCF-7 cell lines was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay.…”