Search

Soulattrolide is a natural coumarin synthesized by the leaves of species of Calophyllum (Calophyllaceae) rain forest trees, including the American C. brasiliense, and the Asian C. teysmanii. Soulattrolide is a potent inhibitor of the reverse transcriptase from HIV‐1 (RT‐HIV‐1), and active against Mycobacterium tuberculosis. However, the effects of this coumarins on other systems, remains to be evaluated. C. brasiliense is used in traditional medicine for the treatment of pain and inflammation. Therefore, we decided to explore the antinociceptive, anti‐inflammatory activity of soulattrolide in mice, as well as, some of its possible effects on the CNS. Soulattrolide showed antinociceptive effects in the writhing test (ED50 = 33.8 mg/kg), as well as, in the formalin test with an ED50 = 7.9, and 22.1 mg/kg for Phases 1 and 2, respectively. The highest dose of soulattrolide (50 mg/kg) induced 40% of antinociception in the hot plate test. Regarding to anti‐inflammatory activity, in the 12‐O‐Tetradecanoylphorbol‐13‐acetate (TPA) test, soulattrolide showed an IC50 = 1.81 μmol/ear, whereas in the myeloperoxidase assay, it showed an inhibition of 87% (1 μmol/ear). Soulattrolide showed sedative effects on the pentobarbital‐induced sleeping time test, and the rotarod test, but lacked antidepressant activity on the tail suspension test. In conclusion, we report for the first time, the antinociceptive effects of soulattrolide in mice, like those of naproxen; soulattrolide also showed mild anti‐inflammatory activity, as well as mild sedative and anxiolytic properties, therefore, it has also activity on the CNS. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to determine the cellular and molecular mechanisms of cell death induced by mammea A/ BA and A/ BB (3 : 1) on K562 cells. Methods These compounds were isolated from C alophyllum brasiliense and its cytotoxicity was tested using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell death was evaluated by Terminal deoxynucleotidyl transferase dUTP nick end labeling ( TUNEL) assay and immunocytofluorescence of active caspase-3. Genotoxicity was tested using comet assay. Lastly, a chemoinformatic analysis was performed with Osiris- Molinspiration software. Key findings The mixture of mammea A/ BA and A/ BB (3 : 1) showed cytotoxic activity against K562 cells ( IC50 = 43.5 μ m). TUNEL positive cells and active caspase-3 were detected after treatment. Genotoxicity of mammea A/ BA and A/ BB on K562 was detected since first hour of treatment. Additionally, mammea A/ BA and A/ BB were found to be in compliance with Lipinski 'rule of 5' suggesting that they possess strong potential of druglikeness. Conclusions The overall results confirm and extend the knowledge about coumarins as an important resource of antitumor drugs, and indicate that these compounds could be used in further preclinical studies against leukaemia. [ABSTRACT FROM AUTHOR]

Calophyllum brasiliense (Clusiaceae) is a big tree from the Tropical Rain Forests of the American continent. The organic extracts from the leaves yielded coumarins of the mammea type: mammea A/BA, A/BB, B/BA, B/BB, C/OA, C/OB, B/BA cyclo F, B/BB cyclo F, and isomammeigin. The triterpenoids friedelin and canophyllol, as well as the biflavonoid amentoflavone, protocatechuic and shikimic acids, were also obtained. Most of the isolated compounds were tested in vitro against K562, U251, and PC3 human tumor cell lines. The coumarins were cytotoxic against the three cell lines, the highest activity was shown by mammea A/BA (3) (IC50 = 0.04 to 0.59 μM). The mixtures of mammea A/BA (3) + A/BB, mammea B/BA + B/BB and mammea C/OA + C/OB were also highly active (IC50 < 4.05 μM). Friedelin was cytotoxic only against PC3, and U251 lines. Inhibition of HIV-1 reverse transcriptase was also assayed in vitro; however, none of the tested compounds (250 μM) prevented the activity of this enzyme. Most of the isolated compounds were also inactive against fourteen bacterial strains; however mammea A/BA + A/BB, and mammea C/OA + C/OB inhibited the growth of Staphylococcus aureus, S. epidermidis and Bacillus subtilis. [Copyright &y& Elsevier]

Background: The current drugs for Chagas Disease caused by the protozoan Trypanosoma cruzi have limited therapeutic potential and are associated with serious side effects. Natural products can aid to develop new chemotherapeutic agents. Several natural coumarins, especially Mammea A/BA, have shown significant activity against T. cruzi and low toxicity on human lymphocytes, but its effectivity on a wide range of strains need to be tested, as well as to deepen in their mode of action and safety.Hypothesis/purpose: To discern the effects and explore the action mechanisms of mammea A/BA and a mixture of mammea coumarins isolated from Calophyllum brasiliense on Mexican strains of T. cruzi belonging to different genotypes and compare its effectivity with the drug benznidazole.Study Design: We evaluated the trypanocidal activity in vitro of mammea A/BA (93.6%), and a mixture of coumarins, mammea A/BA + A/BB + A/BD (86:10:1%) on Mexican T. cruzi strains belonging to different genotypes Ninoa, Querétaro (TcI) and Ver6 (TcVI).Material and Methods: Mammea A/BA and the mixture of coumarins, were isolated from Calophyllum brasiliense, identified by proton NMR and purity determined by HPLC. The in vitro trypanocidal activity was evaluated on mobility, growth recovery, morphology and infectivity of T. cruzi. The cytotoxicity on mammalian cells was compared with benznidazole. The ultrastructure of the treated epimastigotes was analyzed by transmission electron microscopy (TEM).Results: Mammea A/BA and the mixture of coumarins showed high trypanocidal activity, affecting the mobility, growth recovery, morphology, ultrastructure of epimastigotes, and drastically reduce trypomastigotes infectivity on Vero cells. These substances were four times more potent than benznidazole and showed low cytotoxicity and high selectivity index. The TEM showed severe alterations on the plasmatic membrane, nuclear envelope, as well as, mitochondrial swelling, that leads to the death of parasites.Conclusion: Mammea A/BA (93.6%) and a mixture of mammea A/BA + A/BB and A/BD (86: 10: 1%) isolated from the tropical tree C. brasiliense showed higher trypanocidal activity than the current drug benznidazole on three Mexican strains of T. cruzi. These compounds induced severe physiological and morphological alterations. These results suggest their possible use in preclinical studies. [ABSTRACT FROM AUTHOR]

• Mammea A/BA from Calophyllum brasiliense had potent activity against T. cruzi. • Mammea A/BA induced mitochondrial dysfunction, ROS production and DNA fragmentation. • Significant alteration of the cell cycle was observed after exposition to Mammea A/AB. • Increased number of acidic vacuoles were induced by Mammea A/AB. • Together our data suggest apoptosis, autophagy and finally necrosis as action mechanisms of Mammea A/BA. Chagas Disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi which affects 6–8 million people, mostly in Latin America. The medical treatment is based on two nitroimidazole compounds, which have limited effectiveness in the chronic phase of the disease and produce several adverse effects; consequently, there is an urgent need to develop new, safe, and effective drugs. Previous reports had shown that natural coumarins, especially mammea A/BA isolated from the tropical tree Calophyllum brasiliense , is a promissory molecule for developing new drugs, due to its potent activity, higher than benznidazole, selectivity, and its low toxicity in mice. However, its mode of action is still unknown. In the present work, we evaluated the mechanism of action of the coumarin mammea A/BA (93.6%), isolated from the tropical tree C. brasiliense on Querétaro strain (Tc1) of T. cruzi. This compound was tested in vitro on epimastigotes and trypomastigotes of T. cruzi for intracellular esterase activity, plasma membrane integrity, phosphatidylserine exposure, ROS production, mitochondrial membrane potential, caspase-like activity, DNA integrity, cell cycle and autophagy. Mammea A/BA showed a 50% lethal concentration (LC 50) of 85.8 and 36.9 μM for epimastigotes and trypomastigotes respectively. It affected intracellular esterase activity, produced important plasma membrane damage and induced phosphatidylserine exposure. An increase in reactive oxygen species (ROS) and decrease in mitochondrial membrane potential were detected. Caspase-like activity was present in both parasite forms producing DNA integrity damage. This compound also induced a cell cycle arrest in the G1 phase and the presence of autophagy vacuoles. The above data suggest that mammea A/BA induce cell death of T. cruzi by autophagy and apoptosis-like phenomena and support our suggestion that mammea A/BA could be a promising molecule for the development of new drugs to treat Chagas Disease. [ABSTRACT FROM AUTHOR]