Evaluation of cytotoxic, apoptotic, mutagenic, and chemopreventive activities of semi-synthetic esters of gallic acid.

Gallic acid and its derivatives are phenolic compounds widely used as food supplements in the form of capsules, liquid extracts, and ointments owing to their good antioxidant properties. Besides, these compounds are potent inhibitors of fungi, bacteria, and some viruses and possess strong antiproliferative and chemopreventive activities. However, gallic acid derivatives are also known to exert harmful effects like mutagenicity and cytotoxicity. The present study aimed to understand and explore the toxicological risks of these compounds. For this, a series of alkyl gallates with side chains varying from five to eight carbons (pentyl, hexyl, heptyl, and octyl gallates) were evaluated for their cytotoxic and pro-apoptotic potential. In addition, the genotoxic effects of alkyl gallates were measured in HepG2 cells using the single cell gel electrophoresis (SCGE)/comet assay and the cytokinesis-blocked micronucleus (CBMN) test. In both the tests, the substances did not induce any significant differences when compared to the control group. In addition, alkyl gallates exhibited a chemopreventive effect, thereby considerably reducing the mutagenicity caused by H2O2. In conclusion, our results suggest that alkyl gallates are non-genotoxic, non-mutagenic, and pro-apoptotic agents, which may serve as suitable and promising candidates for preventing chemically-induced chromosomal damage.

Alkyl hydroxybenzoic acid derivatives that inhibit HIV-1 protease dimerization.

The therapeutic potential of gallic acid and its derivatives as anti-cancer, antimicrobial and antiviral agents is well known. We have examined the mechanism by which natural gallic acid and newly synthesized gallic acid alkyl esters and related protocatechuic acid alkyl esters inhibit HIV-1 protease to compare the influence of the aromatic ring substitutions on inhibition. We used Zhang-Poorman's kinetic analysis and fluorescent probe binding to demonstrate that several gallic and protecatechuic acid alkyl esters inhibited HIV-1 protease by preventing the dimerization of this obligate homodimeric aspartic protease rather than targeting the active site. The tri-hydroxy substituted benzoic moiety in gallates was more favorable than the di-substituted one in protocatechuates. In both series, the type of inhibition, its mechanism and the inhibitory efficiency dramatically depended on the length of the alkyl chain: no inhibition with alkyl chains less than 8 carbon atoms long. Molecular dynamics simulations corroborated the kinetic data and propose that gallic esters are intercalated between the two N- and C-monomer ends. They complete the ß-sheet and disrupt the dimeric enzyme. The best gallic ester (14 carbon atoms, K(id) of 320 nM) also inhibited the multi-mutated protease MDR-HM. These results will aid the rational design of future generations of non-peptide inhibitors of HIV-1 protease dimerization that inhibit multi-mutated proteases. Finally, our work suggests the wide use of gallic and protocatechuic alkyl esters to dissociate intermolecular ß-sheets involved in protein-protein interactions.

Avaliação das atividades antioxidante, anti e pró-hemolítica do extrato etanólico das folhas de Pterogyne nitens Tul. (Fabaceae-Caesalpinioideae) / Evaluation of antioxidant, anti- and pro-hemolytic activities of ethanol extract from the leaves of Pterogynenitens Tul. (Fabaceae-Caesalpinioideae)

A pesquisa de produtos naturais permite a descoberta de novos princípios ativos, ou ainda, a descoberta de novas atividades para extratos de plantas (amplamente utilizados pela população brasileira) e princípios ativos naturais já conhecidos. Pterogyne nitens é uma planta cuja descrição das atividades é relativamente recente e, portanto, tem no extrato bruto boa fonte para pesquisas na área de produtos naturais. Desta forma, o objetivo deste trabalho foi estudar o perfil antioxidante do extrato bruto etanólico das folhas de P. nitens e possível interferência sobre a hemólise provocada pelo radical AAPH•. No estudo da ação antioxidante das espécies estudadas, ABTS•+, DPPH•, H2O2 e HOCl, encontrou-se os valores de IC50 de 5,0 µg mL-1, 17 µg mL-1, sem ação e 3,9 µg mL-1, respectivamente, valores relativamente baixos e que indicam bom potencial antioxidante. Foram encontradas atividades pró-hemolítica e anti-hemolítica para o extrato de forma concentração-dependente. O extrato estudado mostro boa fonte de moléculas naturais com potencial de ação biológica.

The search for natural products as a widespread practice enables the discovery of new active principles, or the discovery of new activities for plant extracts (extensively used by the population) and natural active principles already known. Pterogynenitensis is a plant whose descriptions of activities are relatively recent and therefore has in its crude extract a good source for research in the field of natural products. Thus, the aim of this study was to evaluate the antioxidant profile of crude ethanol extract from P. nitens leaves and a possible influence on the hemolysis caused by AAPH• radical. For the studied oxidant species, ABTS•+, DPPH•, HOCl and H2O2, the IC50 values were found of 5.0 µg mL-1, 17 µg mL-1, no action at all, and 3.9 µg mL-1, respectively, relatively low values, indicating a good antioxidant potential. Pro- and anti-hemolytic activities were found for the extract in a concentration-dependent way. The studied extract showed to be a good source of natural molecules with potential biological action.