Computational and pharmacological investigation of novel 1,5-diaryl-1,4-pentadien-3-one derivatives for analgesic, anti-inflammatory and anticancer potential.

OBJECTIVES: The novel 1,5-diaryl-1,4-pentadien-3-one derivatives were studied for analgesic, anti-inflammatory and anticancer potential to establish their role in pain, inflammatory disorders and cancer. MATERIALS AND METHODS: Two 1,5- diaryl-1,4-pentadien-3-one derivatives: (1E,4E)- 5-(4-fluoro phenyl)-1-(4-methoxyphenyl)- 2-methylpenta-1,4-dien-3-one (A2K2A17) and (1E,4E)-5-(4-nitrophenyl)-1-(4-nitrophenyl)-2-ethylhexa-1,4-dien-3-one (A11K3A11) were synthesized and characterized via 1H NMR and 13C NMR techniques. Molecular docking, anti-inflammatory, analgesic and anticancer activities were performed using Auto Doc Vina, carrageenan mediated paw edema and formalin induced chronic inflammation, acetic acid induced writhings and hotplate assay and brine-shrimp lethality assay. RESULTS: A2K2A17 and A11K3A11 showed high computational affinities (binding energy > -9.0 Kcal/mol) against COX-1, kappa receptor and braf kinase domain. A2K2A17 and A11K3A11 exhibited moderate docking affinities (binding energy > -8.0 Kcal/mol) against COX-2, human capsaicin receptor, tumor necrosis factor, lipoxygenase, colony stimulating factor, delta receptor, cyclin dependent protein kinase-2, mitogen activated kinase, mu receptor and kit kinase domain. A2K2A17 and A11K3A11 possess low docking affinities (binding energy > -7.0 Kcal/mol) against purinoceptor, platelets-derived growth Factor-1 and vascular-endothelial growth factor. In analgesic activity, A2K2A17 (1-30 mg/kg) and A11K3A11 (1-10 mg/kg) decreased acetic acid induced writhes and prolonged the latency time (P<0.01, P<0.001 vs saline group) respectively. A2K2A17 (10-30 mg/kg) and A11K3A11 (1-10 mg/kg) reduced carrageenan as well as formalin mediated edema (P<0.01, P<0.001). A2K2A17 found effective for cytotoxicity assay with LC50 value 1.5 µg/ml. CONCLUSION: The in silico, in vitro and in vivo studies on A2K2A17 and A11K3A11 reports their computational binding affinities against targets as well as the analgesic, anti-inflammatory and the anticancer effects.

Synthesis, characterization, molecular docking, analgesic, antiplatelet and anticoagulant effects of dibenzylidene ketone derivatives.

In this study dibenzylidene ketone derivatives (2E,5E)-2-(4-methoxybenzylidene)-5-(4-nitrobenzylidene) cyclopentanone (AK-1a) and (1E,4E)-4-(4-nitrobenzylidene)-1-(4-nitrophenyl) oct-1-en-3-one (AK-2a) were newly synthesized, inspired from curcuminoids natural origin. Novel scheme was used for synthesis of AK-1a and AK-2a. The synthesized compounds were characterized by spectroscopic techniques. AK-1a and AK-2a showed high computational affinities (E-value > - 9.0 kcal/mol) against cyclooxygenase-1, cyclooxygenase-2, proteinase-activated receptor 1 and vitamin K epoxide reductase. AK-1a and AK-2a showed moderate docking affinities (E-value > - 8.0 kcal/mol) against mu receptor, kappa receptor, delta receptor, human capsaicin receptor, glycoprotein IIb/IIIa, prostacyclin receptor I2, antithrombin-III, factor-II and factor-X. AK-1a and AK-2a showed lower affinities (E-value > - 7.0 kcal/mol) against purinoceptor-3, glycoprotein-VI and purinergic receptor P2Y12. In analgesic activity, AK-1a and AK-2a decreased numbers of acetic acid-induced writhes (P < 0.001 vs. saline group) in mice. AK-1a and AK-2a significantly prolonged the latency time of mice (P < 0.05, P < 0.01 and P < 0.001 vs. saline group) in hotplate assay. AK-1a and AK-2a inhibited arachidonic acid and adenosine diphosphate induced platelet aggregation with IC50 values of 65.2, 37.7, 750.4 and 422 µM respectively. At 30, 100, 300 and 1000 µM concentrations, AK-1a and AK-2a increased plasma recalcification time (P < 0.001 and P < 0.001 vs. saline group) respectively. At 100, 300 and 1000 µg/kg doses, AK-1a and AK-2a effectively prolonged bleeding time (P < 0.001 and P < 0.01 vs. saline group) respectively. Thus in-silico, in-vitro and in-vivo investigation of AK-1a and AK-2a reports their analgesic, antiplatelet and anticoagulant actions.

Retalho VY de avanço após recidiva de neoplasia perianal: relato de caso e revisão da literatura / V-Y flap of advancement after the recurrence of perineal cancer: case report and literature review

Introdução: O câncer anal é uma doença rara, cuja incidência está aumentando. Os retalhos são opções complexas de fechamento quando abrangem grandes áreas. A região perineal pode ser acometida por extensas lesões, requerendo utilização de retalhos. Relato de Caso: Paciente feminina, 56 anos, diagnosticada com adenocarcinoma anal, foi submetida à cirurgia de amputação abdominoperineal do reto associada à radioterapia pós-operatória há 2 anos. Apresentou recidiva cutânea da lesão neoplásica, com indicação de ampliação de margem cirúrgica para controle da recidiva. Após ampla ressecção com margem de segurança o defeito cutâneo, optou-se por duplo retalho em V-Y com 15 cm de comprimento cada e espessura total do tecido celular subcutâneo (TCS) de região glútea para preenchimento do espaço morto deixado pela ressecção e avanço sobre o defeito. Implementou-se antibioticoprofilaxia endovenosa e profilaxia para trombose venosa profunda. Paciente evoluiu bem do procedimento sem intercorrências. Discussão: Retalho é um tecido que é mobilizado conforme sua anatomia vascular. Retalhos baseados no plexo subdérmico incluem os bipediculados, de avanço (V-Y), retalhos de rotação e transposição. Reconstruções de períneo são indicadas devido a tumores, traumas, infecções, queimaduras ou úlceras de pressão. A região anal é dividida em canal anal e margem anal. Dentre os tipos histológicos de neoplasia na região do canal anal, podem ser citados: carcinoma de células escamosas (histologia mais comum), adenocarcinoma, melanoma, carcinoma de pequenas células e sarcomas. O risco de recidiva locorregional, após tratamento, pode atingir cerca de 30% dos casos e é o padrão de recidiva mais frequente.

Introduction: Anal cancer is a rare disease, with an increasing incidence. Flaps are complex options for closing large areas. The perineal region may be affected by extensive lesions that require the use of flaps for repair. Case Report: A 56-year-old female patient with anal adenocarcinoma underwent abdominoperineal amputation surgery of the rectum with postoperative radiotherapy for 2 years. She had cutaneous recurrence of the neoplastic lesion with indication of surgical margin expansion to control the local recurrence. After extensive resection with safety margins of the skin defect, we selected double V-Y flap of length 15 cm each and a total thickness of the gluteal subcutaneous tissue (ST) to fill up the dead space caused by resection and advancement of the defect. Intravenous antibiotic prophylaxis and deep venous thrombosis prophylaxis were administered. The patient progressed well from the procedure, with no problems. Discussion: A flap is a tissue that is mobilized based on vascular anatomy. Flaps based on the subdermal plexus include bipedicle, advancement (V-Y), rotation, and transposition flaps. Perineum reconstructions are often indicated for tumors, trauma, infections, burns, or pressure sores. The anal region is divided into the anal canal and the anal margin. Among the histological types of anal cancer, the most prevalent are squamous cell carcinoma (most common histology), adenocarcinoma, melanoma, small cell carcinoma, and sarcomas. The risk of regional recurrence after treatment can reach approximately 30% of cases and is the most frequent recurrence pattern.

An antimicrobial diketopiperazine alkaloid and co-metabolites from an endophytic strain of Gliocladium isolated from Strychnos cf. toxifera.

From an endophytic strain of Gliocladium sp. isolated from the Amazonian plant Strychnos cf. toxifera, we obtained the diketopiperazine alkaloid cyclo-(glycyl-L-tyrosyl)-4,4-dimethylallyl ether (1), the steroids ergosterol (2), ergosterol peroxide (3), cerevisterol (4) and the citric acid (5). The AcOEt extract of the fermented broth by Gliocladium sp. showed potent activity against the cancer cell lines MDA-MB435 (human breast cancer cells), HCT-8 (human colorectal cancer cells) and SF-295 (human glioblastoma cancer cells). Compound 1 exhibited a strong antimicrobial activity against Micrococcus luteus at a concentration of 43.4 µM.

High-speed counter-current chromatographic isolation of ricinine, an insecticide from Ricinus communis.

The alkaloid ricinine, an insecticide for leaf-cutting ant (Atta sexdens rubropilosa), was obtained from Ricinus communis. A two-phase solvent system composed of CH(2)Cl(2)/EtOH/H(2)O (93:35:72, v/v/v) was used for high-speed counter-current chromatographic (HSCCC) isolation of ricinine in high yield and with over 96% purity, as determined by liquid and gas chromatography-mass spectrometry (LC-MS and GC-MS). Identification of ricinine was performed by comparison of (1)H NMR, (13)C NMR and LC-MS/MS data.

Isolation of xanthyletin, an inhibitor of ants' symbiotic fungus, by high-speed counter-current chromatography.

Xanthyletin, an inhibitor of symbiotic fungus (Leucoagaricus gongylophorus) of leaf-cutting ant (Atta sexdens rubropilosa), as well as suberosin, seselin and xanthoxyletin were isolated from Citrus sinensis grafted on Citrus limonia. A two-phase solvent system composed of hexane/ethanol/acetonitrile/water (10:8:1:1, v/v) was used for the high-speed counter-current chromatographic isolation of xanthyletin with high yield and over 99% purity as determined by liquid and gas chromatography with mass spectrometry detection. Identifications were performed by UV spectra, IR spectra, (1)H NMR and (13)C NMR.

Polysaccharide fraction of Agaricus brasiliensis avoids tumor-induced IL-10 production and changes the microenvironment of subcutaneous Ehrlich adenocarcinoma.

Subcutaneous Ehrlich tumor-bearing mice were treated with in situ inoculation of a beta-glucan-rich extract of Agaricus brasiliensis (ATF), which reduced tumor growth. Histopathological analysis showed that the tumor masses of control mice (Ehr) presented giant tumor cells and many mitotic figures whereas the tumor tissue obtained from ATF-treated animals (Ehr-ATF) presented a lower frequency of both mitotic and giant cells, associated with a higher frequency of apoptotic cells than Ehr. Analysis of the lymphoproliferative activity of spleen cells showed that the treatment had a suppressive rather than a stimulatory effect. Spleen cells of the Ehr group produced higher in vitro levels of IL-10 than normal controls and this occurrence was partially avoided by treatment with ATF. Analysis of cytokine production by tumor-infiltrating cells (ELISpot) showed that ATF induced a higher number of IFN-gamma-producing cells at 7 and 14days as well as reduction of IL-10-secreting cells at the latter time. Confocal microscopy analysis showed higher intensity of labeling of CD4+ and Mac-3+ cells in ATF-treated mice. Analysis of in situ expression of angiogenic growth factors showed a slight decrease of FGF-2 mRNA in Ehr-ATF animals (7th day) but not of VEGF-A or TGF-beta expression. This fraction could not directly lyse either lymphocytes or tumor cells and we speculate that antitumor effect of ATF could be due to induction of a selective migration of immunocompetent cells from the spleen to the tumor site and to the switch of cytokine production.

Peptaibols of trichoderma.

The fungal genus Trichoderma has various applications in industry and in medicine, and several species have economic importance as sources of enzymes, antibiotics, plant growth promoters, decomposers of xenobiotics, and as commercial biofungicides. Peptaibiotics and peptaibols are a class of linear peptides synthesized by such fungi, and more than 300 have been described to date. Of this class, those compounds exhibiting antimicrobial activity are referred to as antibiotic peptides. In this review, the biosynthesis, fermentation, structure elucidation (by MS and NMR techniques in particular) and biological activity of antibiotic peptides from Trichoderma species are described.

A validated higher-performance liquid chromatography method for quantification of cinchonain Ib in bark and phytopharmaceuticals of Trichilia catigua used as Catuaba.

The hydroalcoholic extract, prepared from authentic chopped barks of Trichilia catigua, was evaluated by high-performance liquid chromatography using a diode array detector (200-400 mn). The crude extract was purified by rotation locular counter-current chromatography and the chloroform fraction obtained was clean-up by solid-phase extraction. With the aim of getting preliminary structure information on-line, the methanol fraction thus obtained was analyzed by gradient elution using the diode array detector coupled to a mass spectrometer. The presence of flavalignan in this extract was inferred by the chromatographic band, in the total ion current trace, that had an [M-H](-) = 451. With this information, cinchonain Ib was isolated as a pure compound from the crude hydroalcoholic extract using a solid-phase extraction procedure for the sample clean-up followed by a semi-preparative separation using the reverse mode of elution. The isolated compound, after complete characterization, was used as an external standard for the development and validation of a method for the analysis of this compound in herbal medicines using the ultraviolet as the detector. The validated method has been successfully applied for quantification of cinchonain Ib in commercialized herbal medicines sold as Catuaba in Brazil and also in standard chopped barks of T. catigua.

Cytotoxicity, genotoxicity and antimutagenicity of hexane extracts of Agaricus blazei determined in vitro by the comet assay and CHO/HGPRT gene mutation assay.

Agaricus blazei Murrill ss. Heinem, known as the sun mushroom or himematsutake, is a basidiomycete native to Brazil, which is popular for its medicinal properties. The aim of this study was to test hexane extracts (one fraction and its four sub-fractions) of A. blazei for bioactivity in cultured mammalian cells (CHO-K1). The comet assay, the colony forming assay (CFA) and CHO/HGPRT gene mutation assay were used respectively to determine genotoxicity, cytotoxicity and antimutagenicity of these extracts at different concentrations. The cells were incubated in culture medium and treated for 3h according to the standard protocol for each assay. The DNA damage-inducing agent ethylmethane sulfonate (EMS) was utilized as the positive control and also in combination with extracts to test for a protective effect. Statistical analysis of the data was performed using analysis of variance (ANOVA) and Tukey's test. A relationship between cytotoxicity and genotoxicity could be established and two extracts EH6B and EH6D showed a protective tendency, while the others did not, with the primary extract EH6 causing the most substantial damage to genetic material. These findings warrant more in-depth studies of the active principles of this mushroom.