posted on 2020-03-16, 18:47authored byVera M.
S. Isca, Ricardo J. Ferreira, Catarina Garcia, Carlos M. Monteiro, Jelena Dinic, Suvi Holmstedt, Vânia André, Milica Pesic, Daniel J. V. A. dos Santos, Nuno R. Candeias, Carlos A. M. Afonso, Patrícia Rijo
The development of
multidrug resistance (MDR) is a major cause
of failure in cancer chemotherapy. Several abietane diterpenes with
antitumoral activities have been isolated from Plectranthus spp. such as 6,7-dehydroroyleanone (DHR, 1) and 7α-acetoxy-6β-hydroxyroyleanone
(AHR, 2). Several royleanone derivatives were prepared
through hemisynthesis from natural compounds 1 and 2 to achieve a small library of products with enhanced anti-P-glycoprotein
activity. Nonetheless, some derivatives tend to be unstable. Therefore,
to reason such lack of stability, the electron density based local
reactivity descriptors condensed Fukui functions and dual descriptor
were calculated for several derivatives of DHR. Additionally, molecular
docking and molecular dynamics studies were performed on several other
derivatives to clarify the molecular mechanisms by which they may
exert their inhibitory effect in P-gp activity. The analysis on local
reactivity descriptors was important to understand possible degradation
pathways and to guide further synthetic approaches toward new royleanone
derivatives. A molecular docking study suggested that the presence
of aromatic moieties increases the binding affinity of royleanone
derivatives toward P-gp. It further suggests that one royleanone benzoylated
derivative may act as a noncompetitive efflux modulator when bound
to the M-site. The future generation of novel royleanone derivatives
will involve (i) a selective modification of position C-12 with chemical
moieties smaller than unsubstituted benzoyl rings and (ii) the modification
of the substitution pattern of the benzoyloxy moiety at position C-6.