Royleanone Analogues from Plectranthus spp. Demonstrate P-gp Inhibition and PKC Modulation
2022
Autori:
Bangay, GabrielleIsca, Vera M. S.
Dos Santos, Daniel J. V. A.
Ferreira, Ricardo J.
Princiotto, Salvatore
Jovanović, Mirna
Pešić, Milica
Rijo, Patricia
Ostala autorstva
Berzal-Herranz, AlfredoSousa, Maria Emília
Tip dokumenta:
Konferencijski prilog (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
The number of multidrug resistant (MDR) cancer cases across the globe is continuing to rise,
such that the search for novel anti-cancer therapeutics is paramount. For instance, the overexpression
of membrane transport proteins, such as P-glycoprotein (P-gp), or the selective modulation of protein
kinases C (PKC) isoforms continues to be a major impediment to effective therapy. Known for
their medicinal properties, species from Plectranthus have been reported to have cytotoxicity against
various cancer cell lines due to diterpenes, such as 7 -acetoxy-6 -hydroxyroyleanone (Roy) and 6,7-
dehydroroyleanone (DeRoy). Based on molecular docking simulations, 10 semi-synthetic derivatives
of Roy that displayed strong P-gp interactions in silico were prepared. The antitumoral activity was
evaluated in resistant human cancer cell lines NCI-H460/R and DLD1-TxR, showing three derivatives
having the most prominent selectivity towards cancer cells, compared to normal lung fibroblasts
MRC5. Moreover, they showed a reduction in P-gp activity in Rho123 accumulation and indicated
P-gp inhibition in the DOX accumulation assay using the same resistant cell lines. Overall, it was
demonstrated that three abietane diterpenoids induced P-gp inhibition in MDR cancer cell lines. As
regards the PKC activity, further analogues were tested as PKC ( , I, , " and ) modulators; one
benzoylated derivative showed the ability to selectively activate PKC- , while the natural compound
DeRoy displayed improved PKC activity, compared with the positive control, in all tested isoforms.
Further investigations are ongoing to prepare analogues of other biologically active diterpenoids to
obtain potential hits as P-gp and PKC modulators.
Ključne reči:
royleanones; diterpenes; P-gp; PKC; analogues; cancerFinansiranje / projekti:
- This research was funded by Fundação para a Ciência e a Tecnologia (FCT, Portugal), through project UIDB/04567/2020, UIDP/04567/2020, UI/BD/151422/2021 & SFHR/BD/137671/2018
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200007 (Univerzitet u Beogradu, Institut za biološka istraživanja 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
U:
- Berzal-Herranz A, Sousa MA, editors. The 8th International Electronic Conference on Medicinal Chemistry; 2022 Nov 1-30; Virtual Event. Basel: MDPI; 2022. p. 144. (Medical Scienece Forum; Vol. 14; No. 1).