Mechanistic aspects of the complete set of hydrolysis and anation reactions of cis- and trans-DDP related to their antitumor activity modeled by an improved ASED-MO approach

 
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Mechanistic aspects of the complete set of hydrolysis and anation reactions of cis- and trans-DDP related to their antitumor activity modeled by an improved ASED-MO approach (EN)

Tsipis, A. C. (EN)

Πανεπιστήμιο Ιωαννίνων. Σχολή Θετικών Επιστημών. Τμήμα Χημείας (EL)
Tsipis, A. C. (EN)

Semi-empirical calculations at an improved modified atom superposition and electron delocalization molecular orbital model (ASED-MO) level of theory have been used to model both the hydrolysis and its microscopic reversible anation reactions of the cis-diammino-dichloro-platinum(II) (cis-DDP) antitumor drug and its biologically inactive trans-isomer. Optimized structures for the reactants and products are reported together with trigonal bipyramidal (TBP) structures relevant to an associative mechanism. The hydrolysis reactions of cis-DDP were found to be endothermic and have to surmount high activation barriers while the reverse anation reactions were exothermic exhibiting low activation barriers. The salient feature of the reaction profiles corresponding to an SN2 mechanism is the formation of weak adducts with square pyramidal (SP) geometries that precede and follow the formation of the near TBP transition states along the reaction coordinate. The computed activation energies and enthalpies of the reactions are in good agreement with available experimental and theoretical data. This provides persuasive support for the reliability of the structural, energetic and electronic data of the complex metal-containing systems delivered by the improved modified ASED-MO approach. The computed interaction energies for the formation of the SP weak adducts are reported for the first time thus being predictions as there are no experimental and other theoretical data available so far for comparisons to be made. Moreover, the reaction profile of the interaction of one and two guanine base molecules with all possible hydrolysis products of cis-DDP, modeling the formation of monofunctional and bifunctional adducts during the cis-DDP/DNA interactions was also investigated at the ASED-MO level of theory. The computed activation barriers of the reactions illustrated that the formation of a monofunctional adduct is mostly favored by the interaction of the cis-[Pt(NH3)2(H2O)Cl]+ hydrolysis product with guanine. (EN)

ASED-MO (EN)

Πανεπιστήμιο Ιωαννίνων (EL)
University of Ioannina (EN)

Journal of Molecular Structure: THEOCHEM (EN)

Αγγλική γλώσσα

2002


Elsevier (EN)



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