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 [1].

Promising bioactive molecules were found in Plectranthus genus, mainly diterpene royleanones [1, 2]. The 7α-acetoxy-6β-hydroxyroyleanone (Roy) is the major constituent of P. grandidentatus acetonic extracts. Several biological activities of Roy were reported in the literature, including antitumoral activity [3]. Moreover, the presence of two free hydroxyl groups (position C-6 and C12) 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-O-benzoylroyleanone (RoyBz) [3], shown selective activation of PKC-δ [5].

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 C-12 and C-6 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.

References:

[1]. Ladeiras D et al. (2016) Curr. Pharm. Des. 22 (12): 1682.[2]. Matias D et al. (2019) ACS Omega. 4: 8094.[3]. Bernardes CES et al. (2018) Mol. Pharm. 15 (4): 1412.[4]. Saraiva L et al., “Roy-Bz: a small molecule activator of Protein Kinase Cdelta (PKCDelta)” Patent Ref PCT/IB2017/050633.[5]. Bessa C et al., Cell Death Dis. 2018, Vol. 9.