Activity to Breast Cancer Cell Lines of Different Malignancy and Predicted Interaction with Protein Kinase C Isoforms of Royleanones
by
Vera M. S. Isca 1,2
, Milan Sencanski 3, Nenad Filipovic 4, Daniel J. V. A. Dos Santos 2, Ana Čipak Gašparović 5, Lucília Saraíva 6, Carlos A. M. Afonso 2, Patrícia Rijo 1,2,* and 
Alfonso T. García-Sosa 7,*
Vera M. S. Isca 1,2, Milan Sencanski 3, Nenad Filipovic 4, Daniel J. V. A. Dos Santos 2, Ana Čipak Gašparović 5, Lucília Saraíva 6, Carlos A. M. Afonso 2, Patrícia Rijo 1,2,* and Alfonso T. García-Sosa 7,*
1
Center for Research in Biosciences & Health Technologies (CBIOS), Universidade Lusófona de Humanidades e Tecnologias, 1749-024 Lisboa, Portugal
2
Instituto de Investigação do Medicamento (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisboa, Portugal
3
Laboratory for Bioinformatics and Computational Chemistry, Institute of Nuclear Sciences VINCA, University of Belgrade, P.O. Box 522, 11001 Belgrade, Serbia
4
Department of Chemistry and Biochemistry, Faculty of Agriculture, University of Belgrade, 11001 Belgrade, Serbia
5
Rudjer Boskovic Institute, Bijenicka 54, HR-10000 Zagreb, Croatia
6
LAQV/REQUIMTE, Laboratório de Microbiologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira n.º 228, 4050-313 Porto, Portugal
7
Institute of Chemistry, University of Tartu, Ravila 14a, 54011 Tartu, Estonia
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(10), 3671; https://doi.org/10.3390/ijms21103671
Received: 30 April 2020 / Revised: 21 May 2020 / Accepted: 21 May 2020 / Published: 23 May 2020
(This article belongs to the Special Issue Computational Studies of Biomolecules)
Plants have been used for centuries to treat several illnesses. The Plectranthus genus has a vast variety of species that has allowed the isolation of cytotoxic compounds with notable activities. The abietane diterpenes 6,7-dehydroroyleanone (DeRoy, 1), 7α-acetoxy-6β-hydroxyroyleanone (Roy, 2), and Parvifloron D (ParvD, 3) were obtained from Plectranthus spp. and showed promising biological activities, such as cytotoxicity. The inhibitory effects of the different natural abietanes (1-3) were compared in MFC7, SkBr3, and SUM159 cell lines, as well as SUM159 grown in cancer stem cell-inducing conditions. Based on the royleanones’ bioactivity, the derivatives RoyBz (4), RoyBzCl (5), RoyPr2 (6), and DihydroxyRoy (7), previously obtained from 2, were selected for further studies. Protein kinases C (PKCs) are involved in several carcinogenic processes. Thus, PKCs are potential targets for cancer therapy. To date, the portfolio of available PKC modulators remains very limited due to the difficulty of designing isozyme-selective PKC modulators. As such, molecular docking was used to evaluate royleanones 1-6 as predicted isozyme-selective PKC binders. Subtle changes in the binding site of each PKC isoform change the predicted interaction profiles of the ligands. Subtle changes in royleanone substitution patterns, such as a double substitution only with non-substituted phenyls, or hydroxybenzoate at position four that flips the binding mode of ParvD (3), can increase the predicted interactions in certain PKC subtypes.
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Keywords:
Plectranthus; royleanones; hemi-synthesis; PKC activity; isozyme-selectivity; molecular interactions
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
MDPI and ACS Style
Isca, V.M.S.; Sencanski, M.; Filipovic, N.; Dos Santos, D.J.V.A.; Čipak Gašparović, A.; Saraíva, L.; Afonso, C.A.M.; Rijo, P.; García-Sosa, A.T. Activity to Breast Cancer Cell Lines of Different Malignancy and Predicted Interaction with Protein Kinase C Isoforms of Royleanones. Int. J. Mol. Sci. 2020, 21, 3671.
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