A theoretical study on mechanism of the anticancer drug camptothecin's E-ring-opening

•The mechanism of CPT's E-ring-opening has been studied by theoretical methods.•E-ring-opening conforms to the addition coupled elimination reaction pathway.•The activation free energies increase as the number of participated water rises.•The solvent effect plays a key role in affecting the reaction.

A reaction mechanism of the anticancer agent camptothecin (CPT)’s E-ring-opening has been studied by DFT method and IEF-PCM solvation model. Our results indicate that under the physiological PH, CPT's E-ring-opening is a spontaneous process, and it conforms to the addition coupled elimination reaction pathway with a proton translocation. The obtained activation free energies in the explicit water model are in agreement with the available experimental values. More than ten reactions have been studied to provide exhaustive analyses of the relationship between structure and reactivity. On the whole, our results accord with the experimental findings and the mechanism we proposed is reasonable.

Graphical abstractA reaction mechanism of the anticancer agent camptothecin (CPT)’s E-ring-opening studied by theoretical methods, which describes the conversion of CPT from an active lactone form to an inactive hydrolyzed carboxylate form.Figure optionsDownload full-size imageDownload high-quality image (230 K)Download as PowerPoint slide