| 1. |
|
|
| 2. |
- Isca, Vera M. S., et al.
(author)
-
Molecular Docking Studies of Royleanone Diterpenoids from Plectranthus spp. as P-Glycoprotein Inhibitors
- 2020
-
In: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 11:5, s. 839-845
-
Journal article (peer-reviewed)abstract
- 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 7 alpha-acetoxy-6 beta-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.
|
|
| 3. |
- Mahammad, S, et al.
(author)
-
Limited cholesterol depletion induces T cell activation and increases the plasma membrane fraction of higher order leading to clustering of signaling molecules
- 2009
-
In: The 49th Annual American Society of Cell Biology Meeting, San Diego, December 2009. ; , s. 2562/M-L20-
-
Conference paper (other academic/artistic)abstract
- The plasma membrane of eukaryotic cells contains nanodomains known as lipid rafts. Cholesterol depletion is a widely used technique for studying lipid rafts and their involvement in cellular processes. Cholesterol depletion has been reported to cause both increased and abolished T cell signaling. The abolished cell signaling upon cholesterol depletion is likely to be caused by substantial cell death as demonstrated by cell viability measurements. We have investigated how cholesterol depletion alters T cell activation by analyzing Jurkat T cells upon extraction of 10, 20, 30, 40 and 50% of total cholesterol using methyl β cyclodextrin (MBCD), a protocol in which cholesterol depletion does not have any adverse effect on cell viability.Upon cholesterol depletion peripheral actin polymerization and aggregation of the lipid raft marker GM1 in the plasma membrane is observed. The aggregation of GM1 upon cholesterol depletion is dependent on signaling protein Lck. The aggregated GM1 domains colocalize with signaling proteins such as Lck and LAT. To confirm that the effects seen by cholesterol depletion using cyclodextrin are actually due to cholesterol depletion and not cyclodextrin treatment itself, control experiments having Jurkat T cells treated with MBCD-cholesterol complexes to keep the cellular cholesterol content at equilibrium. A larger fraction of ordered (lo) plasma membrane is observed upon cholesterol depletion, a study performed by using laurdan. A relative membrane order is given by normalized ratio of the two emission regions termed as general polarization (GP). GP is defined analogously to fluorescence polarization by measuring the intensities (I) between 385 and 470 nm and 480 and 508 nm. Change in the membrane order and increased peripheral actin polymerization indicates that actin polymerization is in correlation to the formation of liquid ordered (lo) domains in the plasma membrane upon cholesterol depletion. Our results conclude that limited cholesterol depletion leads to T cell activation and an increase in the amount of liquid ordered domains in the plasma membrane. This activation is followed by aggregation of GM1 enriched domains.
|
|
| 4. |
|
|
| 5. |
- Garcia, Catarina, et al.
(author)
-
Royleanone Derivatives From Plectranthus spp. as a Novel Class of P-Glycoprotein Inhibitors
- 2020
-
In: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 11
-
Journal article (peer-reviewed)abstract
- Cancer is among the leading causes of death worldwide. One of the most challenging obstacles in cancer treatment is multidrug resistance (MDR). Overexpression of P-glycoprotein (P-gp) is associated with MDR. The growing incidence of cancer and the development of MDR drive the search for novel and more effective anticancer drugs to overcome the MDR problem. Royleanones are natural bioactive compounds frequently found in Plectranthus spp. The cytotoxic diterpene 6,7-dehydroroyleanone (1) is the main component of the P. madagascariensis (Pers.) Benth. essential oil, while 7α-acetoxy-6β-hydroxyroyleanone (2) can be isolated from acetonic extracts of P. grandidentatus Gürke. The reactivity of the natural royleanones 1 and 2 was explored to obtain a small library of new P-gp inhibitors. Four new derivatives (6,7-dehydro-12-O-tert-butyl-carbonate-royleanone (20), 6,7-dehydro-12-O-methylroyleanone (21), 6,7-dehydro-12-O-benzoylroyleanone (22), and 7α-acetoxy-6β-hydroxy-12-O-benzoylroyleanone (23) were obtained as pure with overall modest to excellent yields (21–97%). P-gp inhibition potential of the derivatives 20–23 was evaluated in human non-small cell lung carcinoma NCI-H460 and its MDR counterpart NCI-H460/R with the P-gp overexpression, through MTT assay. Previously prepared diterpene 7α-acetoxy-6β-benzoyloxy-12-O-(4-chloro)benzoylroyleanone (4), has also been tested. The P-gp inhibiting effects of compounds 1–4 were also assessed through a Rhodamine 123 accumulation assay. Derivatives 4 and 23 have significant P-gp inhibitory potential. Regarding stability and P-gp inhibition potential, results suggest that the formation of benzoyl esters is a more convenient approach for future derivatives with enhanced effect on the cell viability decrease. Compound 4 presented higher anti-P-gp potential than the natural diterpenes 1, 2, and 3, with comparable inhibitory potential to Dexverapamil. Moreover, derivative 4 showed the ability to sensitize the resistant NCI-H460/R cells to doxorubicin.
|
|
