Mutagenicity of New Lead Compounds to Treat Sickle Cell Disease Symptoms in a Salmonella/Microsome Assay

A series of phthalimide derivatives planned as drugs candidates to treat the symptoms of sickle cell anemia were evaluated in a mutagenicity test using strains of Salmonella typhimurium TA100 and TA102, without and with addition of S9 mixture, with the aim to identify the best structural requirements for a drug candidate without genotoxic activity. The compounds (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl nitrate (1); (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl nitrate (2); 3-(1,3-dioxo-1,3-dihydro-2H-iso-indol-2-yl)benzyl nitrate (3); 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-hydroxy-benzenesulfonamide (4); 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)benzyl nitrate (5) and 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)phenyl]ethyl nitrate (6) presented mutagenic potency ranging between 0–4,803 revertants/μmol. These results allowed us to propose that a methyl spacer linked to a nitrate ester subunit associated to meta aromatic substitution decreases mutagenicity

Mutagenicactivity of glycoallkaloids from Solanum palinacanthum Dunal (Solanaceae) found in the brazilian cerrado

Solanaceous plants are widely distributed around the world and they are traditionally used as drugs for the treatment of cancer and herpes, and include familiar foods such as potato, tomato and eggplant and some berries popular in Brazil. As part of a program of research on pharmacologically active new molecules, the aim in this study was to assess the mutagenic effects of Solanum palinacanthum, known popularly as joá. The crude 95% ethanol extract and purified solamargine obtained from the fruits of S. palinacanthum Dunal were investigated by the Ames test, using the Salmonella typhimurium strains TA98, TA97a, TA100 and TA102 as test organisms, with and without metabolic activation. The concentrations tested ranged from 0.07 to 15.0 mg/plate for the crude ethanolic extract and from 1.25 to 5.0 mg/plate for the solamargine. The results showed a mutagenic effect of both the extract and the solamargine in the TA98 strain (without metabolic activation). The present study showed the potential mutagenicity and suggests confirming this effect in other models, before recommending their indiscriminate consumption by the population.Colegio de Farmacéuticos de la Provincia de Buenos Aire

Evaluation of mutagenicity and metabolism-mediated cytotoxicity of the naphthoquinone 5-methoxy-3,4-dehydroxanthomegnin from Paepalanthus latipes

AbstractA large number of quinones have been associated with antitumor, antibacterial, antimalarial, and antifungal activities. Results of previous studies of 5-methoxy-3,4-dehydroxanthomegnin, a naphthoquinone isolated from Paepalanthus latipes Silveira, Eriocaulaceae, revealed antitumor, antibacterial, immunomodulatory, and antioxidant activities. In this study, we assessed the mutagenicity and metabolism-mediated cytotoxicity of 5-methoxy-3,4-dehydroxanthomegnin by using the Ames test and a microculture neutral red assay incorporating an S9 fraction (hepatic microsomal fraction and cofactors), respectively. We also evaluated the mutagenic activity in Salmonella typhimurium strains TA100, TA98, TA102, and TA97a, as well as the cytotoxic effect on McCoy cells with and without metabolic activation in both tests. Results indicated that naphthoquinone does not cause mutations by substitution or by addition and deletion of bases in the deoxyribonucleic acid sequence with and without metabolic activation. As previously demonstrated, the in vitro cytotoxicity of 5-methoxy-3,4-dehydroxanthomegnin to McCoy cells showed a significant cytotoxic index (CI50) of 11.9μg/ml. This index was not altered by addition of the S9 fraction, indicating that the S9 mixture failed to metabolically modify the compound. Our results, allied with more specific biological assays in the future, would contribute to the safe use of 5-methoxy-3,4-dehydroxanthomegnin, compound that has showed in previous studies beneficial properties as a potential anticancer drug

In vivo evaluation of anticlastogenicity of extracts from medicinal plants of Miconia genus using the micronucleus test <br> Avaliação in vivo da anticlastogenicidade de extratos de plantas medicinais do gênero Miconia através do teste do micronúcleo

The genus Miconia is comprised of approximately 1000 species. For some of them, biological activities have already been described such as the analgesic and the anti-microbial ones. The purpose of this work was to evaluate the possible protective and cytotoxic effects of the methanolic extract from M. albicans, M. cabucu, M. rubiginosa and M. stenostachya and the chloroformic extract from M. albicans in mice bone marrow cells in 540 mg/kg p.c. dose. The extracts were administered by means of forced feeding and the cyclophosphamide (CPA) was applied intraperitonially one hour after supplementation with extracts. All animals were submitted to euthanasia 30 hours after the treatment. The analyzed cells were extracted from mice bone marrow according to protocol described by Schmid (1975). The cytotoxicity of the extracts was evaluated through the percentage of polychromatic erythrocytes (PCE) in 200 erythrocytes (PCE + NCE). Two thousand PCEs of each animal were analyzed and the micronucleated polychromatic erythrocytes (MNPCEs) frequencies were scored. The results obtained indicated that none of the extracts associated with the CPA showed cytotoxic effect and only the extracts of M. rubiginosa and M. stenostachya showed protective effect to DNA. Chemical analyses of the extracts showed that the four species studied contain mainly flavonoids, phenolic compounds and tannins. The phytochemical characterization of these extracts could contribute to elucidate the protective effect presented only by the species M. rubiginosa and M. stenostachya, besides making it possible the study of other therapeutic activities. O gênero Miconia possui aproximadamente 1000 espécies, e para algumas, já foram descritas atividades biológicas como a analgésica e antimicrobiana. Esse trabalho teve como objetivo avaliar os possíveis efeitos protetores e citotóxicos dos extratos metanólicos de M. albicans, M. cabucu, M. rubiginosa e M. stenostachya e do extrato clorofórmico de M. albicans em células da medula óssea de camundongos na dose de 540 mg/kg p.c. Os extratos foram administrados via gavage e a ciclofosfamida (CPA) foi aplicada intraperitonealmente 1h, após a suplementação com os extratos. Todos os animais foram submetidos à eutanásia 30h após o tratamento. As células analisadas foram retiradas da medula óssea de acordo com protocolo descrito por Schmid (1975). A citotoxicidade dos extratos foi avaliada pela percentagem de eritrócitos policromáticos (PCE) em 200 eritrócitos (PCE + NCE). Foram analisados 2000 PCEs por animal e anotadas as freqüências de MNPCEs. Os resultados obtidos mostraram que nenhum dos extratos associados à CPA apresentou efeito citotóxico e somente os extratos de M. rubiginosa, M. stenostachya mostraram efeito protetor ao DNA. A análise química dos extratos mostrou que as quatro espécies estudadas contêm, principalmente, flavonóides, compostos fenólicos e taninos. A caracterização fitoquímica desses extratos poderia contribuir para elucidação do efeito protetor apresentado somente pelas espécies M. rubiginosa e M. stenostachya, além de possibilitar o estudo de outras possíveis atividades terapêuticas