QSAR studies of macrocyclic diterpenes with P-glycoprotein inhibitory activity

• Autor(a) principal: Sousa, Inês J.
• Data de Publicação: 2013
• Outros Autores: Ferreira, Maria-José U., Molnár, Joseph, Fernandes, Miguel X.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.13/5024
• topic: Quantitative structure–activity relationship; P-glycoprotein; Macrocyclic diterpenes; Multidrug resistance; Multiple linear regression; .; Faculdade de Ciências Exatas e da Engenharia

Multidrug resistance (MDR) represents a major limitation for cancer chemotherapy. There are several mechanisms of MDR but the most important is associated with P-glycoprotein (P-gp) overexpression. The development of modulators of P-gp that are able to re-establish drug sensitivity of resistant cells has been considered a promising approach for overcoming MDR. Macrocyclic lathyrane and jatro phane-type diterpenes from Euphorbia species were found to be strong MDR reversing agents. In this study we applied quantitative structure–activity relationship (QSAR) methodology in order to identify the most relevant molecular features of macrocyclic diterpenes with P-gp inhibitory activity and to deter mine which structural modifications can be performed to improve their activity. Using experimental bio logical data at two concentrations (4 and 40 lg/ml), we developed a QSAR model for a set of 51 bioactive diterpenic compounds which includes lathyrane and jatrophane-type diterpenes and another model just for jatrophanes. The cross-validation correlation values for all diterpenes QSAR models developed for bio logical activities at compound concentrations of 4 and 40 lg/ml were 0.758 and 0.729, respectively. Regarding the prediction ability, we get R2 pred values of 0.765 and 0.534 for biological activities at com pound concentrations of 4 and 40 lg/ml, respectively. Applying the cross-validation test to jatrophanes QSAR models, we obtained 0.680 and 0.787 for biological activities at compound concentrations of 4 and 40 lg/ml concentrations, respectively. For the same concentrations, the obtained R2 pred values for jatro phanes models were 0.541 and 0.534, respectively. The obtained models were statistically valid and showed high prediction ability.