Reactivity of 5a,6-anhydrotetracycline platinum(II) complex with biological nucleophiles: a theoretical study

Abstract

No presente artigo, métodos teóricos foram utilizados para o estudo da interação entre o complexo 5a,6-anidrotetraciclina-dicloro-platina(II) (AHTC-Pt) e os nucleófilos adenina (A), guanina (G), cisteína (Cys) e metionina (Met). A espécie [Pt(AHTC)Cl(H 2 O)] + foi considerada como reagente em todos os processos investigados. Os valores calculados para ∆G a,aq no nível B3LYP/6-311+G(2d,p) foram 21,7 e 20,7 kcal mol -1 para as interações com A e G, respectivamente, os quais estão em acordo com o comportamento esperado, sendo a reação com G mais rápida (∆G a expt = 18,5 kcal mol -1 para G). Para os processos envolvendo os aminoácidos, as barreiras de energia calculadas foram 17,6 (Cys) e 18,5 kcal mol -1 (Met), as quais são ligeiramente menores do que os valores experimentais para a cisplatina (20,5 e 20,2 kcal mol -1 , respectivamente). Esses resultados mostram que a reatividade do complexo AHTC-Pt é comparável a da cisplatina e, portanto, o mesmo pode ser considerado um sistema relevante para o desenvolvimento de novos agentes antitumorais. This paper describes a theoretical analysis of the interaction between 5a,6-anhydrotetracycline platinum(II) complex (AHTC-Pt) and some biological nucleophiles; adenine (A), guanine (G), cysteine (Cys) and methionine (Met). The aquated species [Pt(AHTC)Cl(H 2 O)] + was taken as reagent for the processes studied here. For DNA bases (A and G), the calculated values for ∆G a,aq at the B3LYP/6-311+G(2d,p) level were 21.7 and 20.7 kcal mol -1 for interaction with A and G, respectively, which are in accordance with the expected behavior of faster process involving G. These values are higher than the experimental activation energy for the parent compound cisplatin (18.5 kcal mol -1 for interaction with G). For the process involving the amino-acids, the barriers were 17.6 (Cys) and 18.5 kcal mol -1 (Met), which are lower than the observed values for cisplatin (20.5 and 20.2 kcal mol -1 , respectively). These outcomes show that AHTC-Pt hybrid complex may be considered a promising lead compound in the development of novel anticancer drugs based on platinum complex.

Tetraciclinas e glicilciclinas: uma visão geral

“…36 Antes, nós havíamos mostrado que os mesmos compostos eram ativos em linhagens de bactérias resistentes à tetraciclina. 39 A hipótese de utilizar os complexos de tetraciclina-Pt(II) na quimioterapia do câncer é reforçada pelo estudo teórico realizado recentemente por Dos Santos et al, 50 no qual mostraram que a reatividade do complexo [Pt(AHTC)Cl 2 ] frente a diversos nucleófilos é similar à da cisplatina.…”

Platinum(II) compounds of tetracyclines as potential anticancer agents: cytotoxicity, uptake and interactions with DNA

“…The same authors have shown that the reactivity of the Pt II compound of anhydrotetracycline towards several nucleophiles is similar to that of cisplatin. 26 Tetracyclines also exhibit pharmacological properties other than antimicrobial activity. An example of interest in cancer therapy is the inhibition by doxycycline and other chemically modified tetracyclines of matrix metalloproteinases, which are members of the zincdependent metallopeptidases and implicated in major stages of cancer progression.…”

DFT/TDDFT investigation of the stepwise deprotonation in tetracycline: pKa assignment and UV–vis spectroscopy

“…Several theoretical investigations on tetracyclines have been reported, using ab initio [29][30][31][32] and DFT [33][34][35][36][37][38][39][40] calculations, dealing with their possible conformations [35][36][37], their complexation with different metals [33,39,40], and their vibrational and NMR spectroscopy [34,35]. Regarding the electronic spectra, the simulation of the absorption spectra has been performed for the neutral tetracycline [2] and for the related anhydrotetracycline by semiempirical calculations [41].…”