Isatin derivatives as DNA minor groove-binding agents: a structural and theoretical study

Abstract

Cervical cancer is the fourth most frequently occurring malignancy in women worldwide. It is of vital importance to find new alternatives for the treatment of this disease. Isatin is a natural compound with a molecular versatile architecture, which allows its use in a wide range of fields in medicinal chemistry. Many of these compounds have been evaluated as anticancer agents in many cell lines; however, their action mechanism remains uncertain. In this work, we investigated 55 isatin derivatives with reported cytotoxic activity against the human cervical cancer cell line (HeLa), to propose their action mechanism. As a first step, to unravel the key structural features of these compounds that result in anticancer activity over the HeLa line, a QSAR study was done. Our QSAR model revealed that the positive ionizable groups, planar molecular shape and hydrophobic character define the potency of the compounds. The statistical parameters values of our QSAR model were Q2 = 87.5, R2 = 91.24, s = 0.165 and F = 52.08; additionally, the QUIK, redundancy and overfitting rules were applied. The predictive ability of the model was evaluated using 30% of the compounds in this study as the external set, obtaining a Q2ext = 79.99 value. From these results, a molecular similarity analysis (MSA) of the isatin derivatives with a series of DNA intercalating and minor groove-binding agents, and further docking with DNA, suggested that the molecular action mechanism of these compounds may be as DNA minor groove-binder agents in assays with the HeLa cell line.