Efeito de grupos espectadores na hidrólise de diésteres fosfóricos. Estudos da hidrílise do bis-2-piridil fosfato e das reações do fármaco deferoxamina com mono-e triéster de fosfato

Abstract

Esta tese de doutoramento compreende: (i) Estudo das reações de deferoxamina (DFO) com 2,4-dinitrofenil fosfato (DNPP) e dietil 2,4-dinitrofenil fosfato (DEDNPP). Em comparação com as reações de hidrólise espontânea, DFO acelera aproximadamente 107 vezes a quebra do DEDNPP, em contraste com a reação do DNPP, acelerada modestamente por DFO. A elevada reatividade na quebra do DEDNPP foi também observada com o pesticida paraoxon metílico, sugerindo uma utilização adicional para o DFO: em casos de intoxicação por compostos organofosforados. (ii) Efeito de grupos espectadores na hidrólise de diésteres de fosfato. Os dados de hidrólise de quatro diésteres foram correlacionados como gráfico de Brønsted, que fornece um NLG igual a -0,031 a 100°C. Esses resultados trazem uma nova relação linear de energia livre à literatura, a qual indica que a sensibilidade à natureza dos grupos espectadores na hidrólise de diésteres de fosfato é mínima. (iii) Reatividade do bis-2-piridil fosfato (DPP). A constante de velocidade para a reação de hidrólise do DPP- é cerca de 10000 vezes maior do que o previsto para a hidrólise espontânea de um diéster de fosfato diarílico com grupo de saída de pKa similar, a 25ºC. As evidências computacionais e cinéticas mostram que a reação de hidrólise espontânea de DPP- ocorre com catálise básica-geral intramolecular pelo nitrogênio piridínico do grupo espectador.<br>

Abstract : This thesis includes: (i) Kinetic study of the reactions of the drug Deferoxamine (DFO) with phosphate esters 2,4-dinitrophenyl phosphate (DNPP) and diethyl 2,4-dinitrophenyl phosphate (DEDNPP). Compared with the spontaneous hydrolysis of the substrate, DFO promotes rate enhancements of about 107-fold in the dephosphorylation of DEDNPP, in contrast to the reaction with the monoester DNPP, which is only slightly promoted by DFO. The high reactivity in the dephosphorylation of the model triester DEDNPP was also observed in the reaction with pesticide methyl paraoxon (dimethyl 4-nitrophenyl phosphate), which suggests a possible additional use of drug DFO: reactivation of acetilcolinesterase in acute poisoning with organophosphorus compounds. (ii) Non-leaving group effect in phosphate diester hydrolysis. Two novel phosphate diesters were synthesized (2,4-dinitrophenyl phenyl phosphate and 2,4-dinitrophenyl 4-nitrophenyl phosphate) and hydrolyzed at 100ºC. Data for the hydrolysis of four phosphate diesters with the same leaving group (2,4-dinitrophenol) but different spectator groups (methyl, phenyl, 4-nitrophenyl and 2,4-dinitrophenyl) were analyzed in terms of a Brønsted relationship depending on the non-leaving group, and the bNLG obtained was -0,031 ± 0,001, at 100°C. The results introduce a new linear free energy relationship (LFER) into the literature and indicate a minimal dependence of phosphate diester hydrolysis upon the nature of the nonleaving group. (iii) Reactivity of di-2-pydridyl phosphate (DPP). The rate constant for the hydrolysis of the anionic species DPP-, at 25°C, is 10000 times higher than expected for the hydrolysis of a simple diaryl phosphate diester with a leaving group of similar pKa. Theoretical calculations and kinetic evidence (including the hydrolysis of phosphate monoester 2-pyridyl phosphate PP, and the reaction of DPP with hydroxylamine), combined with an accurate mechanistic study, show that DPP- hydrolysis occurs through an intramolecular general base catalysis promoted by the pyridyl nitrogen of the non-leaving group.