Exploring the Potential of Oleanolic Acid Dimers-Cytostatic and Antioxidant Activities, Molecular Docking, and ADMETox Profile.

The presented work aimed to explore the potential of oleanolic acid dimers (OADs): their cytostatic and antioxidant activities, molecular docking, pharmacokinetics, and ADMETox profile. The cytostatic properties of oleanolic acid (1) and its 14 synthesised dimers (2a-2n) were evaluated against 10 tumour types and expressed as IC50 values. Molecular docking was performed with the CB-Dock2 server. Antioxidant properties were evaluated with the CUPRAC method. ADMETox properties were evaluated with the ADMETlab Manual (2.0) database. The results indicate that the obtained OADs can be effective cytostatic agents, for which the IC50 not exceeded 10.00 for many tested cancer cell lines. All OADs were much more active against all cell lines than the mother compound (1). All dimers can inhibit the interaction between the 1MP8 protein and cellular proteins with the best results for compounds 2f and 2g with unsaturated bonds within the linker. An additional advantage of the tested OADs was a high level of antioxidant activity, with Trolox equivalent for OADs 2c, 2d, 2g-2j, 2l, and 2m of approximately 0.04 mg/mL, and beneficial pharmacokinetics and ADMETox properties. The differences in the DPPH and CUPRAC assay results obtained for OADs may indicate that these compounds may be effective antioxidants against different radicals.

Oleanolic Acid Dimers with Potential Application in Medicine-Design, Synthesis, Physico-Chemical Characteristics, Cytotoxic and Antioxidant Activity.

The present work aimed to obtain a set of oleanolic acid derivatives with a high level of cytotoxic and antioxidant activities and a low level of toxicity by applying an economical method. Oleanolic acid was alkylated with α,ω-dihalogenoalkane/α,ω-dihalogenoalkene to obtain 14 derivatives of dimer structure. All of the newly obtained compounds were subjected to QSAR computational analysis to evaluate the probability of the occurrence of different types of pharmacological activities depending on the structure of the analysed compound. All dimers were tested for cytotoxicity activity and antioxidant potential. The cytotoxicity was tested on the SKBR-3, SKOV-3, PC-3, and U-87 cancer cell lines with the application of the MTT assay. The HDF cell line was applied to evaluate the tested compounds' Selectivity Index. The antioxidant test was performed with a DPPH assay. Almost all triterpene dimers showed a high level of cytotoxic activity towards selected cancer cell lines, with an IC50 value below 10 µM. The synthesised derivatives of oleanolic acid exhibited varying degrees of antioxidant activity, surpassing that of the natural compound in several instances. Employing the DPPH assay, compounds 2a, 2b, and 2f emerged as promising candidates, demonstrating significantly higher Trolox equivalents and highlighting their potential for pharmaceutical and nutraceutical applications. Joining two oleanolic acid residues through their C-17 carboxyl group using α,ω-dihalogenoalkanes/α,ω-dihalogenoalkenes resulted in the synthesis of highly potent cytotoxic agents with favourable SIs and high levels of antioxidant activity.

The Effect of Cream and Gel Vehicles on the Percutaneous Absorption and Skin Retention of a New Eugenol Derivative With Antioxidant Activity.

The effect of cream and gel vehicles containing clove water on skin permeability was compared for a new eugenol derivative (eugenyl dichloroacetate-EDChA) with antioxidant activity. In vitro permeation experiments were conducted in a Franz cell with porcine skin. The cumulative mass and skin accumulation of EDChA were investigated and compared. The antioxidative capacity of the studied vehicles was determined by using the diphenylpicrylhydrazyl (DPPH) free radical reduction method. The antioxidant activity (evaluated with DPPH, ABTS, and the Folin-Ciocalteu methods) of the fluid that penetrated through the pig skin and of the fluid obtained after the skin extraction, were also determined. For comparison, eugenol was also tested. The results of this work could contribute to the development of vehicles with antioxidant potential estimated after 24 h of conducting the experiment, which indicates long-term protection against reactive oxygen species (ROS) in the deeper layers of the skin. The waste water from the clove buds steam distillation -contains several valuable biologically active compounds, and its use is environmentally friendly. We observed that gel vehicles were the best enhancer of skin permeation for both eugenol and its derivative. In most cases, -similar cumulative masses of eugenol and its ester were found in the acceptor fluid. The accumulation of EDChA was higher for cream vehicles in relation to the parent eugenol when applied onto the skin. The greatest amounts of eugenol were accumulated in the skin when these compounds were used in gel vehicles.

Enhancement of the Antioxidant and Skin Permeation Properties of Betulin and Its Derivatives.

This study investigated the antioxidant activity DPPH, ABTS, and Folin-Ciocalteu methods of betulin (compound 1) and its derivatives (compounds 2-11). Skin permeability and accumulation associated with compounds 1 and 8 were also examined. Identification of the obtained products (compound 2-11) and betulin isolated from plant material was based on the analysis of 1H- NMR and 13C-NMR spectra. The partition coefficient was calculated to determine the lipophilicity of all compounds. In the next stage, the penetration through pig skin and its accumulation in the skin were evaluated of ethanol vehicles containing compound 8 (at a concentration of 0.226 mmol/dm3), which was characterized by the highest antioxidant activity. For comparison, penetration studies of betulin itself were also carried out. Poor solubility and the bioavailability of pure compounds are major constraints in combination therapy. However, we observed that the ethanol vehicle was an enhancer of skin permeation for both the initial betulin and compound 8. The betulin 8 derivative showed increased permeability through biological membranes compared to the parent betulin. The paper presents the transformation of polycyclic compounds to produce novel derivatives with marked antioxidant activities and as valuable intermediates for the pharmaceutical industry. Moreover, the compounds contained in the vehicles, due to their mechanism of action, can have a beneficial effect on the balance between oxidants and antioxidants in the body, minimizing the effects of oxidative stress. The results of this work may contribute to knowledge regarding vehicles with antioxidant potential. The use of vehicles for this type of research is therefore justified.

Enhancement of the antioxidant and skin permeation properties of eugenol by the esterification of eugenol to new derivatives.

The aim of the study was to determine the antioxidant activity and assess the lipophilicity and skin penetration of eugenyl chloroacetate (EChA), eugenyl dichloroacetate (EDChA), and eugenyl trichloroacetate (ETChA). Identification of the obtained products was based on gas chromatography (GC), infrared spectroscopy (FTIR/ATR), gas chromatography coupled with mass spectrometry (GC-MS), and the analysis of 13C-NMR and 1H-NMR spectra. The antioxidative capacity of the derivatives obtained was determined by the DPPH free radical reduction method, while the octanol/water partition coefficient (shake-flask method) was tested to determine the lipophilicity of these compounds. In the next stage of testing EDChA and ETChA-(compounds characterized by the highest degree of free radical scavenging), the penetration of DPPH through pig skin and its accumulation in the skin were evaluated. For comparison, penetration studies of eugenol alone as well as dichloroacetic acid (DChAA) and trichloroacetic acid (TChAA) were also carried out. The antioxidant activity (DPPH, ABTS, and Folin-Ciocalteu methods) of the fluid that penetrated through pig skin was also evaluated. The in vitro pig skin penetration study showed that eugenol derivatives are particularly relevant for topical application. The obtained derivatives were characterized by a high level of antioxidant activity estimated after 24 h of conducting the experiment, which indicates long-term protection against reactive oxygen species (ROS) in the deeper layers of the skin.

Advances in Chemistry and Pharmacology of Triterpenoid Synthetic Dimers.

This review focuses on advances in chemistry and pharmacology of synthetic triterpenoid dimers, obtained from natural compounds. Synthetic triterpenoid dimers are divided into specific subgroups based on the structure of main triterpenoid monomeric skeleton. Synthetic triterpenoid derivatives of dimeric structure can be obtained through the covalent linkage of the C-3 hydroxyl or another group, via the C-2 atom or the C-17 carboxyl group (mainly anhydrides, amides or esters). Some triterpenes can undergo chemical transformations leading to the formation of cyclic dimers or other types of dimers. Most of the obtained triterpenoid dimers have been subjected to pharmacological tests evaluating their biological activity, mainly antiviral (HIV-1 RT, HCVpp, VSVpp, HIV-RT-C8166-CCR5), cytotoxic (against e.g. 388, MCF-7, SF-268, NCIH460, KM20L2, DU-145, Hep-G2, A549, BGC-823, PC-3), anti-inflammatory (iNOS, RAW 264.7) and antidiabetic (RMGPa inhibition). The authors also reported the ability of some of the obtained cyclic triterpenoid dimers to recognize anions and to form self-assembled structures.