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Kinetic and mechanistic aspects of ligand substitution on cis- diaqua (cis-1,2-diaminocyclohexane)platinum(II) with three glycine-containing dipeptides

Posted on 7. August, 2014.

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The discovery of cisplatin as an anticancer agent marks the beginning of the upsurge of interest in the use of metal complexes in cancer chemotherapy. However, cisplatin has a narrow spectrum of activity, and its clinical use is limited by undesirable side effects, including nephrotoxicity, ototoxicity, neurotoxicity, nausea, vomiting, and myelosuppression.

The continuing interest and stimulation has been triggered and guided by two objectives: first, to develop new metal complexes having superior spectra of activities, lower toxicities, better therapeutic indices, and higher solubilities than the presently existing drugs; and second, to understand the mechanistic features of the actions of metal complexes in vivo from the model reactions in vitro
Thus, further investigations have been carried out to synthesise “the second generation platinum drugs” with improved toxicological profiles and “third generation drugs” overcoming cisplatin resistance.

The kinetics of the interaction of glycyl-L-valine(L1-L′H), glycyl-L-isoleucine (L2-L′H) and glycyl-L-glutamine(L3-L′H) with cis-[Pt(cis-dach)(OH2)2]2+(dach=1,2-diaminocyclohexane) have been studied spectrophotometrically as a function of [cis-[Pt(cis-dach)(OH2)2]2+], [ligand], pH and temperature at constant ionic strength, where the complex exists predominantly as the diaqua species and the dipeptides as a zwitterion. The substitution reactions show two consecutive steps: the initial is the ligand-assisted anation and the subsequent step is chelation. The activation parameters for both steps were evaluated using Eyring’s equation. The low ∆H1 and large negative value of ∆S1 as well as ∆H2and ∆S2 indicate an associative mode of activation for both the aqua ligand substitution processes. The products of the reactions have been characterised using IR and ESI-mass spectroscopic analysis. The title complex is already established as an anticancer drug; but its reactivity with all biomolecules will confirm its therapeutic activity (i.e. its efficacy versus toxicity).

Authors: Sumon Ray, Roshni Sarkar (Sain), Animesh Chattopadhyay and Alak K. Ghosh
Department of Chemistry, The University of Burdwan, Burdwan 713104, India

Keywords: platinum(II), dipeptides, kinetics, mechanism, anation, ligand substitution

Read the full article in Progress in Reaction Kinetics and Mechanism, Volume 39, Number 2, 2014, pp. 122-136.

DOI:10.3184/146867814X13981545064892

Image: Spectra of the starting complex (1), glycyl-L-valine (L1-L′H) substituted complex (2), glycyl-L-isoleucine (L2
-L′H) substituted complex (3), glycyl-L-glutamine (L3-L′H) substituted complex (4); [complex 1]=2×10–4 mol dm–3, [dipeptides]=4×10–3 mol dm– 3, pH=4.0, and cell used=1 cm quartz.