M. F. Simões

In vitro antimicrobial activity of royleanone derivatives against Gram-positive bacterial pathogens.

Infections caused by multiresistant bacterial pathogens are a significant problem worldwide, turning the search for natural compounds to act as alternatives to antibiotics of major importance. The aim of the present study was to investigate the in vitro antimicrobial activity of 7α‐acetoxy‐6β‐hydroxyroyleanone (1), isolated from Plectranthus grandidentatus (Lamiaceae), and 11 additional royleanone abietane derivatives of 1 (2–12) against important Gram‐positive human bacterial pathogens. Results showed that the aromatic and alkylic esters 2, 3 and 5 are more active than 1 against Enterococcus and Staphylococcus (minimum inhibitory concentration (MIC) values ranging from 0.98 to 62.50 µg/mL). Moreover, 7α‐acetoxy‐6β‐hydroxy‐12‐O‐(4‐chloro)benzoylroyleanone (2) gave rise to a new antibacterial‐prototype (MIC values of 3.91–15.63 µg/mL against Staphylococcus and of 0.98–3.91 µg/mL against Enterococcus). The results showed that the compounds under analysis also present antimicrobial activity against resistant bacteria. The hydrophobic extra‐interactions with bacterial targets seem to play an important role on the activity of royleanones derivatives. Copyright

Isopimarane diterpenoids from Aeollanthus rydingianus and their antimicrobial activity

Four acyloxy-isopimarane derivatives along with two known isopimarane diterpenoids, the flavone cirsimaritin and the sterols beta-sitosterol and stigmasterol were isolated from the aerial parts of Aeollanthus rydingianus. The structures of the compounds were established on the basis of spectroscopic analysis and chemical evidence. The isolated substances were screened for antimicrobial activity against Gram-positive and Gram-negative bacteria and a yeast strain. 19-Acetoxy-7,15-isopimaradien-3beta-ol and 7,15-isopimaradien-19-ol showed minimum inhibitory concentration (MIC) values of 3.90-15.62 microg/ml for Staphylococcus aureus and of 7.81microg/ml for Enterococcus hirae.

Antiparasitic Activity of Diterpenoids Against Trypanosoma cruzi.

Twenty-seven diterpenes, including abietanes, labdanes, abeoabietanes, halimanes, and pimaranes, have been evaluated against epimastigote and intracellular amastigote forms of Trypanosoma cruzi and also against LC5 and NCTC cell lines. Royleanones (3, 4, and 5) and a further abietane (12), obtained by purification of Plectranthus spp. extracts, were the most active compounds on epimastigotes, showing IC50 values similar (1.73 µg/mL, 12) or even lower (0.39, 0.99, and 1.20 µg/mL, 3, 4, and 5 respectively) than the positive control nifurtimox (2.3 µg/mL). On intracellular amastigotes, abietanes 3, 4, and 5 showed a significant activity with IC50 values of 0.83, < 0.31, and 0.62 µg/mL, respectively, but were less potent than the positive control nifurtimox (IC50 < 0.16 µg/mL). Compounds 3, 4, and 5 were not cytotoxic to LC5 and NCTC 929 cells at 1 µg/mL.

Discovery of a small-molecule protein kinase Cδ-selective activator with promising application in colon cancer therapy

Protein kinase C (PKC) isozymes play major roles in human diseases, including cancer. Yet, the poor understanding of isozymes-specific functions and the limited availability of selective pharmacological modulators of PKC isozymes have limited the clinical translation of PKC-targeting agents. Here, we report the first small-molecule PKCδ-selective activator, the 7α-acetoxy-6β-benzoyloxy-12-O-benzoylroyleanone (Roy-Bz), which binds to the PKCδ-C1-domain. Roy-Bz potently inhibited the proliferation of colon cancer cells by inducing a PKCδ-dependent mitochondrial apoptotic pathway involving caspase-3 activation. In HCT116 colon cancer cells, Roy-Bz specifically triggered the translocation of PKCδ but not other phorbol ester responsive PKCs. Roy-Bz caused a marked inhibition in migration of HCT116 cells in a PKCδ-dependent manner. Additionally, the impairment of colonosphere growth and formation, associated with depletion of stemness markers, indicate that Roy-Bz also targets drug-resistant cancer stem cells, preventing tumor dissemination and recurrence. Notably, in xenograft mouse models, Roy-Bz showed a PKCδ-dependent antitumor effect, through anti-proliferative, pro-apoptotic, and anti-angiogenic activities. Besides, Roy-Bz was non-genotoxic, and in vivo it had no apparent toxic side effects. Collectively, our findings reveal a novel promising anticancer drug candidate. Most importantly, Roy-Bz opens the way to a new era on PKC biology and pharmacology, contributing to the potential redefinition of the structural requirements of isozyme-selective agents, and to the re-establishment of PKC isozymes as feasible therapeutic targets in human diseases.

Plectranthus madagascariensis phytosomes: formulation optimization: Fitossomas de Plectranthus madagascariensis: otimização da formulação

Medicinal plants have been a reliable source of bioactive natural products with potential pharmaceutical applications. The delivery of those bioactive agents into nanosystems is considered a promising strategy for the optimization of their pharmacologic effects. This work describes the preparation of phytosomes containing a bioactive extract from Plectranthus madagascariensis and optimization of the preparation method. Different formulations and process parameters were studied. It was observed that smaller and more uniform particles were obtained using acetone as solvent, a reaction time of two hours, and the addition of 2.5% molar concentration of cholesterol. The optimally prepared phytosomes had a diameter of 191.3 ± 75.3 nm with a polydispersity index of 0.243 ± 0.18, and a spherical shape with amorphous appearance. These nanosystems were able to encapsulate 92.8% of the extract, as evaluated by HPLC, relative to 7α,6β-dihydroxyroyleanona, the main extract component. This study suggests a future application of those phytosomes in the delivery of bioactive agents with therapeutic interest.