Development of inclusion complex based on cyclodextrin and oxazolidine derivative

Abstract Oxazolidine derivatives (OxD) have been described as third-line antibiotics and antitumoral agents. The inclusion complexes based on cyclodextrin could improve the solubility and bioavailability of these compounds. A novel synthetic OxD was used, and its inclusion complexes were based on 2-hydroxy-beta-cyclodextrin (2-HPßCD). We conducted an in silico study to evaluate the interaction capacity between OxD and 2-HPßCD. Characterization studies were performed through scanning electron microscopy (SEM), Fourier-transformed infrared (FTIR), nuclear magnetic resonance spectroscopy (1H-NMR), X-ray diffraction (XRD), and thermal analyses. A kinetic study of the OxD was performed, including a cytotoxicity assay using peripheral blood mononuclear cells (PBMCs). The maximum increment of solubility was obtained at 70 mM OxD using 400 mM 2-HPßCD. SEM analyses and FTIR spectra indicated the formation of inclusion complexes. 1H-NMR presented chemical shifts that indicated 1:1 stoichiometry. Different thermal behaviors were obtained. The pharmacokinetic profile showed a short release time. Pure OxD and its inclusion complex did not exhibit cytotoxicity in PBMCs. In silico studies provided a foremost insight into the interactions between OxD and 2-HPßCD, including a higher solubility in water and an average releasing profile without toxicity in normal cells

Cytotoxic activity of extracts from Tecoma species and isolated lignans

Abstract A phytochemical study of Tecoma genus (Bignoniaceae) was accomplished by antitumor activity of ethanolic extracts. Species of this genus are composed of small shrubs often used as ornamental plants. The Tecoma stans species is used in folk medicine for different purposes. Recent work shows in vitro anticancer activity against human breast cancer. The ethanolic extracts from leaves and trunks of Tecoma casneifolia, T. garrocha, T. stans var. angustata and T. stans var. stans were tested in vitro. The assays used were against line tumor cells by the MTT method and the most active extracts were further studied. In this way, the ethanolic extract from T. stans var. stans trunks presented the higher cytotoxicity against the tumor cell lines studied (CC50 0.02 to 0.55 µg/ml) when compared to the other extracts tested (CC50 0.08 to 200.0 µg/ml). Accordingly, this extract was selected for chromatographic fractionation from which five known lignans were isolated. Further, paulownin, paulownin acetate, sesamin, olivil and cycloolivil were identified using 13C and 1H NMR, IR, UV and spectroscopy and spectrometric MS techniques. These isolated compounds were tested and exhibited CC50 ranging from 13.01 to100.0 µg/ml which is superior to the ethanolic extract of trunk of T. stans

Planejamento, síntese, modelagem molecular e avaliação biológica de novos potenciais inibidores duais HDAC/ MMP não-hidroxamatos / Design, synthesis, molecular modeling and biological evaluation of novel potential non-hydroxamate dual HDAC/ MMP inhibitors

A inibição de alvos específicos como metaloproteinase de matriz (MMP) e histona desacetilase (HDAC) é amplamente estudada para impedir o progresso do câncer. Foi estabelecido que a inibição concomitante de MMP e HDAC é eficaz no combate de tumores sólidos e hematológicos. Ambos os alvos possuem um íon Zn2+ em seu sítio ativo, fundamental para a atividade destas enzimas. A alta afinidade dos inibidores conhecidos de MMP e de HDAC é conferida, principalmente, por um potente grupo ligante de zinco (ZBG). O ácido hidroxâmico é o ZBG mais potente conhecido atualmente, entretanto, este apresenta instabilidade farmacocinética, levando a ineficácia e genotoxicidade em testes clínicos. Frente a este contexto, o presente trabalho teve como objetivo o planejamento, síntese, modelagem molecular e avaliação biológica de novos inibidores duais MMP/HDAC não-hidroxamatos. Os compostos foram planejados utilizando estratégias de hibridação molecular, a partir de arcabouços provenientes inibidores de HDAC e MMP, gerando compostos arilsulfonamídicos com variações no tipo de ZBG inserido e na sua respectiva posição relativa na estrutura geral. Foram sintetizados sete análogos, em duas a três etapas reacionais, utilizando métodos de sulfonilação e acoplamento com agentes condensantes, partindo dos ésteres para e meta aminobenzoicos. Os rendimentos globais variaram de 25% a 55% e os produtos obtidos foram caracterizados por RMN 1H e 13C, LC/MS, CLAE e ponto de fusão. Os compostos tiveram sua atividade citotóxica avaliada em células HOG (oligodendroma) e T98G (glioblastoma), dentre os quais o 6a, que possui o ZBG 2-amino anilida, foi o mais promissor, apresentando atividade nas duas linhagens na casa de nM. Ensaios de coordenação com Fe2+ comprovaram a capacidade quelante dos análogos contendo ácido hidroxâmico e dos demais compostos citotóxicos, 4a e 4b (ZBG-2, salicilal-hidrazona), o que não foi observado para o composto 6a. Os estudos de ancoramento molecular permitiram sugerir um modo de interação para todos os ZBG propostos frente aos respectivos alvos (HDAC e MMP), sendo observado que o ZBG 4 (2-amino anilida) faria a interação de modo monodentado com a HDAC, enquanto não seria possível o encaixe no sítio catalítico da MMP. Conclui-se, portanto, que o planejamento proposto permitiu a obtenção de compostos promissores como antitumorais, e que a substituição do ácido hidroxâmico por outros ZBG fornece moléculas ativas frente a células tumorais. Entretanto, a avaliação biológica frente à MMP e HDAC é necessária para confirmar o mecanismo de ação proposto

Inhibition of specific targets such as matrix metalloproteinase (MMP) and histone deacetylase (HDAC) is extensively studied regarding arrest cancer growth. Particularly, concomitant inhibition of MMP and HDAC is effective against solid and hematologic tumors. Both targets have an ion Zn2+ at their catalytic site, which is essential for respective enzymatic activity. High affinity of known MMP and HDAC inhibitors is mainly provided by a potent zinc binding group (ZBG). Hydroxamic acid is the most potent ZBG currently known; however, it presents low pharmacokinetics stability, which results in its ineffectiveness and genotoxicity along clinical trial. So, the aim of this work comprised the design, synthesis, molecular modeling and biological evaluation of novel potential non-hydroxamate dual HDAC/ MMP inhibitors. Compounds were designed by molecular hybridation, employing scaffolds from HDAC and MMP inhibitors, which provided arylsulfonamides with variation about the ZBG type and its respective relative position in the general structure. Seven compounds were synthesized, in two to three reaction steps, through methods that comprise sulfonilation and coupling with condensing agents, using para and meta-aminobenzoic esters as starting material. Compounds showed global yields around 25-55 % and were characterized by 1H and 13C NMR, LC/MS, HPLC and melting point. Compounds were evaluated about their cytotoxicity against HOG (oligodendroma) and T98G (glioblastoma) cells, which 6a, with ZBG 2-aminobenzamide, was the most promising molecules, presenting activity against both cell lines at nM range. Coordination assays with Fe2+ proved the chelating capacity of hydroxamate analogues as well as the cytotoxic compounds, 4a and 4b (ZBG-2, salicylal-hydrazone), which was not observed about 6a. Molecular docking allowed to suggest an interaction model for all proposed ZBG with the respective targets (MMP and HDAC), showing that (ZBG-4) 2-aminobenzamide interacts with HDAC by monodentate way, but does not docks at MMP catalytic site. We conclude that the proposed design allowed obtaining promising compounds as antitumors agents, and the replacement of hydroxamic acid by other ZBG provide active molecules against tumor cells. However, biological evaluation against MMP and HDAC is necessary to confirm the proposed action mechanism

Compostos carbonílicos α, ß-insaturados e hidrazonas sintéticas como antiparasitários / α, ß-Unsaturated carbonyl compounds and Synthetic hydrazones as antiparasitics

Apesar da grande relevância médica e social, e por serem responsáveis por grande parte das mortes em países subdesenvolvidos e em desenvolvimento as doenças negligenciadas (DN), ainda, não apresentam terapêutica eficaz. Dentre as diversas DN, doenças como a doença de Chagas, a Leishmaniose visceral e a malária, se destacam no cenário nacional, por terem alta incidência e prejuízos sociais. Os fármacos disponíveis para o tratamento destas parasitoses, apresentam alta toxicidade e, em alguns casos, resistência por parte dos parasitas. Assim sendo, faz-se necessário o planejamento e desenvolvimento de novos agentes quimioterápicos mais seguros e eficazes. Dentre as diferentes estratégias de planejamento de fármacos, selecionamos o planejamento de fármacos baseado na estrutura do ligante - LBDD (Ligand-Based Drug Design) - como base para desenvolvimento deste trabalho. Nesta estratégia, utiliza-se o conhecimento de moléculas (ligantes) e de suas atividades biológicas conhecidas previamente determinadas experimentalmente, como protótipos para a busca de novas entidades químicas com atividade biológica semelhante ou melhorada. Sendo assim, o presente trabalho teve como objetivo a síntese e avaliação biológica de moléculas bioativas para o tratamento de doenças parasitárias. Baseando-se no conhecimento prévio da atividade antiparasitária de compostos carbonílicos α,ß-insaturados e hidrazonas, foram sintetizados séries de compostos destas classes químicas na busca de novos agentes quimioterápicos. Os compostos obtidos foram avaliados contra a forma epimastigota de Trypanosoma cruzi, promastigota de Leishmania donovani, amastigota de Leishmania infantum e, também, determinou-se o seu grau de citotoxicidade (CC50) frente a células de macrófago humanos diferenciado (THP-1). As 31 moléculas obtidas foram caracterizadas por técnicas de ponto de fusão, RMN 1H e RMN 13C e avaliada sua pureza por HPLC. Os compostos da classe da cinamoil-hidrazonas apresentaram-se como promissores antiparasitários, mostrando atividade frente a forma promastigota (Leishmania donovani), 4 dos 12 compostos foram ativos (IC50= 1,27 - 13,68 µM) e frente a forma amastigota (Leishmania infantum), 10 dos 12 compostos apresentaram atividade (9,09 - 63,5 µM). Mesmo apresentando citotoxicidade moderada (CC50 = 8,83 - 87,47 µM), os compostos obtiveram valores inferiores ao fármaco de referência (doxorubicina: CC50 = 0,26 µM). Diante do exposto, o planejamento de fármacos realizado por LBDD mostrou-se bem-sucedido, pois a classe de cinamoil-hidrazonas mostrou-se promissora como antiparasitários, visto sua atividade na escala de baixo micromolar e moderada citotoxicidade em células humanas. Esses resultados assinalam que a classe de compostos descrita está passível a continuar sendo investigada no intuito de aprimorar os protótipos obtidos na busca de novos agentes quimioterápicos antiparasitários e desvendar os mecanismos de ação leishmanicida

Despite to the great medical and social relevance and the amount of deaths in underdeveloped and developing countries, neglected diseases (ND) still do not have an effective therapy. Among the various ND, illnesses such as Chagas disease, visceral leishmaniasis and malaria holds a great importance in the Brazilian scenario due to high incidence and social damage. The drugs available for the treatment of these parasitosis present high toxicity and, in some cases, resistance by the pathogens. Thus, the planning and development of new, safer and more effective chemotherapeutic substances are urgent needed. Among the different drug planning strategies, we selected ligand-based drug design (LBDD) as the basis for the development of this work. In this strategy, we use the knowledge of molecules (ligands) and their known biological activities previously determined experimentally, as prototypes to search for new chemical entities with similar or improved biological activity. Therefore, the present work aimed the synthesis and biological evaluation of bioactive molecules for the treatment of parasitic diseases. Based on previous knowledge of the antiparasitic activity of α,ß-unsaturated and hydrazone carbonyl compounds, series of compounds of these chemical classes were synthesized in search of new chemotherapeutic agents. The compounds obtained were evaluated against the epimastigote form of Trypanosoma cruzi, Leishmania donovani promastigote, Leishmania infantum amastigote and their cytotoxicity (CC50) against differentiated human macrophages (THP-1). The 31 molecules obtained were characterized by melting point, 1 H NMR and 13C NMR techniques and their purity were characterized by HPLC. The cinnamoyl hydrazone class compounds showed promising antiparasitic activity, showing activity against promastigote form (L. donovani), 4 of 12 compounds were active (IC50 = 1.27 - 13.68 µM) and amastigote form (L. infantum), 10 of the 12 compounds showed activity (9.09 - 63.5 µM). Even presenting moderate cytotoxicity (CC50 = 8.83 - 87.47 µM), the compounds had values below the reference drug (doxorubicin: CC50 = 0.26 µM). Considering the results, LBDD drug planning proved to be successful and the class of cinnamoyl hydrazones were promising as antiparasitics due to its activity in low micromolar scale and moderate cytotoxicity in human cells. These results indicate that the described class of compounds can be further investigated in order to improve the prototypes obtained in the search for new antiparasitic chemotherapeutic agents and to unravel the mechanisms of action of leishmanicidal molecules

Biological activity of synthesized 5-{1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}-2-mercapto-1, 3, 4-oxadiazole derivatives demonstrated by in silico and BSA binding studies

We synthesized a series of compounds bearing pharmacologically important 1,3,4-oxadiazole and piperidine moieties. Spectral data analysis by 1H-NMR, 13C-NMR, IR and EI-MS was used to elucidate the structures of the synthesized molecules. Docking studies explained the different types of interaction of the compounds with amino acids, while bovine serum albumin (BSA) binding interactions showed their pharmacological effectiveness. Antibacterial screening of these compounds demonstrated moderate to strong activity against Salmonella typhi and Bacillus subtilis but only weak to moderate activity against the other three bacterial strains tested. Seven compounds were the most active members as acetyl cholinesterase inhibitors. All the compounds presented displayed strong inhibitory activity against urease. Compounds 7l, 7m, 7n, 7o, 7p, 7r, 7u, 7v, 7x and 7v were highly active, with respective IC50 values of 2.14±0.003, 0.63±0.001, 2.17±0.006, 1.13±0.003, 1.21±0.005, 6.28±0.003, 2.39±0.005, 2.15±0.002, 2.26±0.003 and 2.14±0.002 µM, compared to thiourea, used as the reference standard (IC50 = 21.25±0.15 µM). These new urease inhibitors could replace existing drugs after their evaluation in comprehensive in vivo studies.

Development, in vitro biocompatibility, and antitumor efficacy of acetic acid-modified Cordyceps sinensis polysaccharide nanoparticle drug delivery system

Docetaxel-loaded acetic acid conjugated Cordyceps sinensis polysaccharide (DTX-AA-CSP) nanoparticles were prepared through dialysis and their release rates in vitro, particle sizes, zeta potentials, drug loading capacities, and encapsulation efficiencies were characterized for the synthesis of AA-modified CSPs from traditional Chinese medicine Cordyceps sinensis (Berk.) Sacc. Then, the AA-modified CSPs were characterized by 1H-NMR and FT-IR. Furthermore, the biocompatibility of the delivery carrier (AA-CSP nanoparticles) was assessed on human umbilical vein endothelial cells. In vitro antitumor activity studies on DTX-AA-CSP nanoparticles were conducted on the human liver (HepG2) and colon cancer cells (SW480). The DTX-AA-CSP nanoparticles were spherical and had an average size of 98.91±0.29 nm and zeta potential within the −19.75±1.13 mV. The encapsulation efficiency and loading capacity were 80.95%±0.43% and 8.09%±0.04%, respectively. In vitro, DTX from the DTX-AA-CSP nanoparticles exhibited a sustained release, and the anticancer activities of DTX-AA-CSP nanoparticles against SW480 and HepG2 were significantly higher than those of marketed docetaxel injection (Taxotere®) in nearly all the tested concentrations. The AA-CSP nanoparticles showed good biocompatibility. This study provided a promising biocompatible delivery system for carrying antitumor drugs for cancer therapy

Effect of prodigiosin on the alleviation of the intestinal inflammation of weaned rats based on 1H-NMR spectroscopy study and biochemistry indexes

Weaning results in intestinal dysfunction, mucosal atrophy, transient anorexia, and intestinal barrier defects. In this study, the effect of prodigiosin (PG) on the intestinal inflammation of weaned rats was investigated by using 1H-NMR spectroscopy and biochemistry indexes to regulate the intestinal metabolism. After administration for 14 days, the body mass of the PG group was increased by 1.29- and 1.26-fold compared with those of the control and alcohol groups, respectively, using a dose of 200 µg PG·kg-1 body weight per day. PG increased organic acid content and decreased moisture, pH values, and free ammonia in feces. In addition, PG alleviated the intestinal inflammation of weaned rats. The analysis of 1H-NMR signal peak attribution and the model validation of metabolic data of feces contents showed that PG significantly affected the metabolism of small molecular compounds in the intestinal tract of weaned rats. This study presents the promising alternative of using PG to alleviate intestinal inflammation effectively in the intestinal tract of weaned rats.

3T magnetic resonance spectroscopy as a powerful diagnostic modality for assessment of thyroid nodules

ABSTRACT Objective: Magnetic resonance spectroscopy (MRS) is a powerful tool for structural studies of chemical compounds and biomolecules and also documented promising findings as a potential imaging technology in thyroid oncology. This prospective study was to ascertain the clinical significance of 3 Tesla MRS in the evaluation of patients with thyroid nodules (TNs) as an ancillary diagnostic technique for thyroid carcinoma. Materials and methods: Magnetic resonance spectroscopy at 3T at echo- times (TEs) 136 and 270 ms was carried out on 15 patients with total number of 32 TNs larger than 1 cm3, which all were surgically resected. Choline (Chol) to creatine (Cr) ratio was assessed at 136 and 270 TEs on each nodule and a receiver operating characteristic (ROC) curve was used to determine optimal cut-off point. The findings were compared with histopathology of thyroid specimens. Results: There were 23 benign and 9 malignant lesions (7 papillary and 2 follicular thyroid carcinomas). The mean values of Chol/Cr at 136 and 270 TEs was 2.28 ± 3.65 and 1.52 ± 1.67 respectively and the difference between benign and malignant nodules was only significant at 136 TEs. The study revealed that Chol/ Cr ratio cut-off point of 2.5 best correlates with histopathology results (sensitivity = 75%; specificity = 100%; PPV = 100%; NPV= 92%). Conclusion: This preliminary study showed that 3T magnetic resonance spectroscopy might be a specific modality for the evaluation of thyroid nodules in differentiation of benign from malignant thyroid tissue. However, a larger series would give much greater confidence that this state-of-the-art technology will worth pursuing in clinical practice.

Disfunção aguda de cabo-eletrodo atrial secundária a acometimento cardíaco por amiloidose / Acute atrial lead dysfunction secondary to cardiac amyloidosis

A amiloidose cardíaca, uma doença rara, pode cursar com insuficiência cardíaca por infiltração das paredes atrial e ventricular, dificultando também sense e limiares adequados quando do implante de marcapasso. Relatamos o caso de uma paciente que apresentou curso atípico, com rápida infiltração da parede atrial e perda da função ventricular, apesar da apresentação inicial com ecocardiograma e ressonância magnética normais. O caso ilustra o acometimento progressivo da doença de base em diversos aspectos cardíacos, inicialmente no sistema de condução atrioventricular, progredindo para maior fibrose atrial e acometimento miocárdico difuso. Os métodos complementares de ecocardiograma e ressonância magnética aumentaram o grau de suspeição da doença e nos permitiram fazer o diagnóstico específico

Cardiac amyloidosis, a rare disease, may lead to heart failure caused by infiltration of the atrial and ventricular walls, making it difficult to obtain sensed atrial stimulation and adequate thresholds at the time of pacemaker implantation. We report the case of a patient with an atypical outcome, rapid atrial wall infiltration and loss of ventricular function, despite the initial presentation with normal echocardiogram and MRI. This case illustrates the progression of the baseline disease, initially in the atrioventricular conduction system, leading to greater atrial fibrosis and diffuse myocardial involvement. The complementary echocardiogram and magnetic resonance imaging improved the level of suspicion of the disease and enabled us to make a specific diagnosis

7-epi-griffonilide, a new lactone from Bauhinia pentandra: complete 1H and 13C chemical shift assignments

ABSTRACT A new lactone, 7-epi-griffonilide (1), and six known compounds, 2, 3a - 3c, 4a and 4b, were isolated from the leaves of Bauhinia pentandra (Fabaceae). The structures elucidation of 1 and 2 were based on detailed 2D NMR techniques and spectral comparison with related compounds, leading to complete assignment of the 1H and 13C NMR spectra.

1H-MRS study on the metabolites of first dorsal interossei / 法医学杂志

OBJECTIVE@#To estimate the application of prognosis evaluation of ulnar nerve injury by 1H-magnetic resonance spectroscopy (1H-MRS).@*METHODS@#The metabolites of first dorsal interossei (FDI) of two hands from 12 healthy volunteers and 1 volunteer with complete ulnar nerve injury were detected by 1H-MRS and the data were statistically analyzed.@*RESULTS@#For the FDI of healthy adults, the female peaks area of extra-myocellular lipids (EMCL) was higher than the male (P < 0.05); There was no significant difference in Cho, Cr and intra-myocellular lipids (IMCL) between male and female (P > 0.05); There was no significant difference in all the peaks area between the left and right hand (P > 0.05). The EMCL peak of the injury side was higher than that of the healthy side, and the area of FDI was reduced in the volunteer with ulnar nerve injury.@*CONCLUSION@#Noninvasive and quantitative detection of 1H-MRS may be valuable for prognosis evaluation of peripheral nerve injury.