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Design and molecular docking studies of new potential PKC-δ activators based on royleanone scaffold
Vera M. S. Isca 1, 2 , Epole Ntungwe 2 , Joana Tavares 2 , Filipa Siopa 1 , Joana Almeida 3 , Lucilia Saraiva 3 , Mattia Mori 4 , Maurizio Botta 4 , Carlos A. M. Afonso 1 , Patricia Rijo * 1, 2
1  Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Portugal
2  Center for Research in Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, Lisboa, Portugal
3  LAQV/REQUIMTE, Departamento de Ciências Biológicas, Faculdade de Fármacia da Universidade do Porto, Portugal
4  Dipartimento di Biotecnologie, Chimica e Farmacia, Università di Siena, Italy

Published: 30 October 2019 by MDPI AG in 5th International Electronic Conference on Medicinal Chemistry session ECMC-5
10.3390/ECMC2019-06297
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 [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.

Keywords: Plectranthus; Roy; derivatives; PKC- δ; antitumoral activity; molecular docking
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