Design and molecular docking studies of new potential PKC-δ activators based on royleanone scaffold

Abstract

The huge impact of cancer is a big concern nowadays. Protein Kinases (PKCs) are attractive anticancer targets due to their involvement in several processes of carcinogenesis. Particularly, the isoform δ (PKC-δ) acts as tumor suppressor in colon cancer, one of the most dominant cancers and cause of cancer mortality worldwide. Promising bioactive molecules were found in Plectranthus genus, mainly diterpene royleanones. The 7α-acetoxy-6β-hydroxyroyleanone (Roy) is the major constituent of P. grandidentatus. Several biological activities of Roy were reported in the literature, including antitumoral activity. Moreover, the presence of two free hydroxyl groups in Roy structure drawn our attention to the possibility of preparing new derivatives with enhanced cytotoxic activity. In fact, in a previous work, the patented diterpene 6β-benzoyloxy-12-Obenzoylroyleanone (RoyBz) shown selective activation of PKC-δ. The aim of the present work is to prepare new potential PKC-δ activators from derivatization of Roy. Thus, Roy and RoyBz assisted the design of theoretical derivatives, through modification of the hydroxyl groups. Molecular docking simulations were carried out against the 3D structure of human PKC-δ regulatory domain, to identify the potential PKC-δ activators. The most promising compounds accepted by docking simulations are currently been prepared by hemi-synthesis using Roy as starting material for structure-activity relationships.