Molecular docking as a tool to design new royleanone derivatives for colon cancer therapy based on PKC-δ modulation

Cancer is one of the most common causes of death worldwide. Many efforts have been made to develop more effective chemotherapeutic drugs. Protein Kinases (PKCs) have wide ranging effects in crucial processes of tumorigenesis and metastatic dissemination. PKC-δ behaves as tumor suppressor in colon cancer, one of the most prevalent cancers and a leading cause of cancer mortality worldwide [1].

Plectranthus genus (Lamiaceae) is a good source of cytotoxic compounds. Abietane diterpenes isolated from this genus have revealed promising anticancer activity [2] particularly as PKC modulators [3]. 7α-Acetoxy-6β-hydroxyroyleanone (Roy, [Fig. 1]) obtained from P. grandidentatus exhibits biological properties including antitumoral activity[4]. Thus, Roy is a potent lead molecule for future drug development with the ultimate purpose of modulate the PKCs. A small library of Roy derivatives prepared by us, was tested on a yeast-based screening assay, and showed promising ability to activate PKC isoforms. Furthermore, the patented 6β-benzoyloxy-12-O-benzoylroyleanone (Roy-Bz) was obtained by semi-synthesis of Roy. This derivative has shown selective modulation in PKC-δ and consequently potently inhibits the proliferation of colon cancer cells [3].

In this work, several theoretical derivatives of Roy were designed through modification of the C-12 and C-6 hydroxyl groups. In addition, molecular docking simulations were carried out against the 3D structure of PKC-δ. These results allowed the identification of the most promising compounds for PKC-δ modulation. Based on the docking achievements new hemi-synthetic abietanes are currently in study for structure-activity relationships and new drug development based on the royleanone scaffold.