α-Glucosidase and PTP-1B Inhibitors from Malbranchea dendritica.

An extract from a PDB static culture of Malbranchea dendritica exhibited α-glucosidase and PTP-1B inhibitory activities. Fractionation of the active extract led to the isolation of gymnoascolide A (1), a γ-butenolide, and xanthones sydowinin A (2), sydowinin B (3), and AGI-B4 (4), as well as orcinol (5). Compound 1 exhibited important inhibitory activity against yeast α-glucosidase (IC50 = 0.556 ± 0.009 mM) in comparison to acarbose (IC50 = 0.403 ± 0.010 mM). Kinetic analysis revealed that 1 is a mixed-type inhibitor. Furthermore, compound 1 significantly reduced the postprandial peak in mice during a sucrose tolerance test at the doses of 5.16 and 10 mg/kg. Compound 1 was reduced with Pd/C to yield a mixture of enantiomers 1a and 1b; the mixture showed similar activity against α-glucosidase (IC50 = 0.396 ± 0.003 mM) and kinetic behavior as the parent compound but might possess better drug-likeness properties according to SwissADME and Osiris Property Explorer tools. Docking analysis with yeast α-glucosidase (pdb: 3A4A) and the C-terminal subunit of human maltase-glucoamylase (pdb: 3TOP) predicted that 1, 1a, and 1b bind to an allosteric site of the enzymes. Compounds 1-5 were evaluated against PTP-1B, but only xanthone 3 moderately inhibited in a noncompetitive fashion the enzyme with an IC50 of 0.081 ± 0.004 mM. This result was consistent with that of docking analysis, which revealed that 3 might bind to an allosteric site of the enzyme. From the inactive barley-based semisolid culture of M. dendritica, the natural pigment erythroglaucin (6) and the nucleosides deoxyadenosine (7), adenosine (8), thymidine (9), and uridine (10) were also isolated and identified.

Synthesis and Cytotoxic Activity of Combretastatin A-4 and 2,3-Diphenyl-2H-indazole Hybrids.

Cancer is the second leading cause of death, after cardiovascular diseases. Different strategies have been developed to treat cancer; however, chemotherapy with cytotoxic agents is still the most widely used treatment approach. Nevertheless, drug resistance to available chemotherapeutic agents is still a serious problem, and the development of new active compounds remains a constant need. Taking advantage of the molecular hybridization approach, in the present work we designed, synthesized, and tested the cytotoxic activity of two hybrid compounds and seven derivatives based on the structure of combretastatin A-4 and 2,3-diphenyl-2H-indazole. Practical modifications of reported synthetic protocols for 2-pheny-2H-indazole and 2,3-dipheny-2H-indazole derivatives under microwave irradiation were implemented. The cytotoxicity assays showed that our designed hybrid compounds possess strong activity, especially compound 5, which resulted even better than the reference drug cisplatin against HeLa and SK-LU-1 cells (IC50 of 0.16 and 6.63 µM, respectively), and it had similar potency to the reference drug imatinib against K562 cells. Additionally, in silico and in vitro studies strongly suggest tubulin as the molecular target for hybrid compound 5.

Synthesis of Curcuminoids and Evaluation of Their Cytotoxic and Antioxidant Properties.

Curcumin (1) and ten derivatives (2-11) were synthesized and evaluated as cytotoxic and antioxidant agents. The results of primary screening by Sulforhodamine B assay against five human cancer cell lines (U-251 MG, glioblastoma; PC-3, human prostatic; HCT-15, human colorectal; K562, human chronic myelogenous leukemia; and SKLU-1, non-small cell lung cancer) allowed us to calculate the half maximal inhibitory concentration (IC50) values for the more active compounds against HCT-15 and K562 cell lines. Compounds 2 and 10 were the most active against both cell lines and were more active than curcumin itself. Thiobarbituric acid reactive substances (TBARS) assay showed that 7 has potent activity; even stronger than curcumin, α-tocopherol, and quercetin.

Evidence of the anti-Helicobacter pylori, gastroprotective and anti-inflammatory activities of Cuphea aequipetala infusion.

ETHNOPHARMACOLOGICAL RELEVANCE: Cuphea aequipetala (Lythraceae) is a medicinal plant highly appreciated in Mexico to treat stomach ailments such as pain and burning sensation, stomach infections, ulcers, diarrhea, dysentery, and different types of tumors and bruises. In this work, the infusion of aerial parts of this plant (CAI) was investigated for its polypharmacological potential. MATERIALS AND METHODS: In vitro anti-Helicobacter pylori activity was assessed by broth dilution method. Pharmacological studies included acute toxicity in mice using Lorke´s model, anti-inflammatory activity by xylene and TPA induced ear edema assay, as well as gastroprotection with ethanol-induced gastric ulcer model. DPPH and ABTS assays were used to determine antioxidant capacity. Polyphenols and flavonoid contents were determined by Folin-Ciocalteu method and AlCl3 reaction, respectively. RESULTS: CAI showed good anti-Helicobacter pylori activity with a MIC of 125µg/mL. The infusion was not toxic according to Lorke's model with a LD50 greater than 5g/kg. CAI exhibited low anti-edematogenic action in the models assayed. Oral administration of 300mg/kg CAI significantly reduced gastric lesions by 87.9%. The effect was reversed only by indomethacin and N-ethylmaleimide demonstrating the role of endogenous prostaglandins and sulfhydryl compounds in gastroprotection. Total phenolic and flavonoid contents of CAI were 109.9mg GAE/g DW and 28.1mg QE/g DW, respectively, and the infusion exhibited a good antioxidant activity that is thought to play a role in its biological activity. The analysis of a preliminary fractionation of the infusion indicates that the complete extract conserves all its pharmacological activities in contrast to fractionated extracts. CONCLUSIONS: Cuphea aequipetala is a promising native herb in an integral therapy for the treatment of bacterial or non-bacterial gastric ulcer because it possesses some anti-inflammatory properties, as well as exhibits good gastroprotective and antibacterial effects. It represents an important source for the isolation of anti-Helicobacter pylori compounds. This work provides ethnopharmacological evidence that supports the traditional use of this species.

Contribution to the ethnopharmacological and anti-Helicobacter pylori knowledge of Cyrtocarpa procera Kunth (Anacardiaceae).

ETHNOPHARMACOLOGICAL RELEVANCE: Cyrtocarpa procera Kunth (Anacardiaceae) is a Mexican endemic tree; its bark has been traditionally employed in Mexico since prehispanic times to relieve digestive disorders. AIM OF THE STUDY: To perform an acute evaluation of the toxicity, gastroprotective, and anti-inflammatory properties, as well as the anti-Helicobacter pylori action of C. procera bark extracts, in order to determine polypharmalcological activities. MATERIALS AND METHODS: Five different polarity extracts (hexanic, CH(2)Cl(2), CH(2)Cl(2)-MeOH, methanolic, and aqueous) were prepared. Each of them was evaluated in the following acute mice models: toxicity Lorke test, ethanol-induced gastric ulcer, TPA-induced ear edema; and the in vitro anti-H. pylori activity with a broth dilution method. RESULTS: None of the extracts were toxic under acute administration. The methanolic, hexanic, and aqueous extracts possess remarkable gastroprotective activity. All the extracts inhibit H. pylori growth, being the hexanic the most active, and only this one showed significant anti-inflammatory effect. CONCLUSIONS: This work demonstrates that C. procera bark has polypharmacological activities; which makes it a promising asset to the development of an integral treatment for gastritis or peptic ulcer related or not to H. pylori. Our findings contribute to the ethnopharmacological knowledge about this species.