Publications by authors named "Ivan R Pitta"

32 Publications

Advances in Synthesis and Medicinal Applications of Compounds Derived from Phthalimide.

Curr Org Synth 2020 ;17(4):252-270

Nucleus of Research in Therapeutical Innovation Suely Galdino (NUPIT SG), Bioscience Center, Federal University of Pernambuco, Recife, Brazil.

Phthalimide derivatives have been presenting several promising biological activities in the literature, such as anti-inflammatory, analgesic, antitumor, antimicrobial and anticonvulsant. The most well-known and studied phthalimide derivative (isoindoline-1,3-dione) is thalidomide: this compound initially presented important sedative effects, but it is now known that thalidomide has effectiveness against a wide variety of diseases, including inflammation and cancer. This review approaches some of the recent and efficient chemical synthesis pathways to obtain phthalimide analogues and also presents a summary of the main biological activities of these derivatives found in the literature. Therefore, this review describes the chemical and therapeutic aspects of phthalimide derivatives.
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http://dx.doi.org/10.2174/1570179417666200325124712DOI Listing
July 2021

Synthesis, Antitumor Activity and Molecular Docking Studies on Seven Novel Thiazacridine Derivatives.

Comb Chem High Throughput Screen 2020 ;23(5):359-368

Laboratory of Design and Drug Synthesis (LPSF), Nucleus of Research in Therapeutical Innovation Suely Galdino (NUPIT SG), Biosciences Center, Federal University of Pernambuco, Recife, Brazil.

Aim And Objective: In the last decades, cancer has become a major problem in public health all around the globe. Chimeric chemical structures have been established as an important trend on medicinal chemistry in the last years. Thiazacridines are hybrid molecules composed of a thiazolidine and acridine nucleus, both pharmacophores that act on important biological targets for cancer. By the fact it is a serious disease, seven new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione derivatives were synthesized, characterized, analyzed by computer simulation and tested in tumor cells. In order to find out if the compounds have therapeutic potential.

Materials And Methods: Seven new 3-acridin-9-ylmethyl-thiazolidine-2,4-dione derivatives were synthesized through Michael addition and Knoevenagel condensation strategies. Characterization was performed by NMR and Infrared spectroscopy techniques. Regarding biological activity, thiazacridines were tested against solid and hematopoietic tumoral cell lines, namely Jurkat (acute T-cell leukemia); HL-60 (acute promyelocytic leukemia); DU 145 (prostate cancer); MOLT-4 (acute lymphoblastic leukemia); RAJI (Burkitt's lymphoma); K562 (chronic myelogenous leukemia) and normal cells PBMC (healthy volunteers). Molecular docking analysis was also performed in order to assess major targets of these new compounds. Cell cycle and clonogenic assay were also performed.

Results: Compound LPSF/AA-62 (9f) exhibited the most potent anticancer activity against HL-60 (IC50 3,7±1,7 μM), MOLT-4 (IC50 5,7±1,1 μM), Jurkat (IC50 18,6 μM), Du-145 (IC50 20±5 μM) and Raji (IC50 52,3±9,2 μM). While the compound LPSF/AA-57 (9b) exhibited anticancer activity against the K562 cell line (IC50 51,8±7,8 μM). Derivative LPSF/AA-62 (9f) did not interfere in the cell cycle phases of the Molt-4 lineage. However, the LPSF/AA-62 (9f) derivative significantly reduced the formation of prostate cancer cell clones. The compound LPSF/AA-62 (9f) has shown strong anchorage stability with enzymes topoisomerases 1 and 2, in particular due the presence of chlorine favored hydrogen bonds with topoisomerase 1.

Conclusion: The 3-(acridin-9-ylmethyl)-5-((10-chloroanthracen-9-yl)methylene)thiazolidine-2,4-dione (LPSF/AA-62) presented the most promising results, showing anti-tumor activity in 5 of the 6 cell types tested, especially inhibiting the formation of colonies of prostate tumor cells (DU-145).
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http://dx.doi.org/10.2174/1386207323666200319105239DOI Listing
May 2021

New Peroxisome Proliferator-Activated Receptor Agonist (GQ-11) Improves Wound Healing in Diabetic Mice.

Adv Wound Care (New Rochelle) 2019 Sep 9;8(9):417-428. Epub 2019 Aug 9.

Department of Clinical and Toxicological Analysis, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil.

Chronic wounds associated with diabetes are an important public health problem demanding new treatments to improve wound healing and decrease amputations. Monocytes/macrophages play a key role in sustained inflammation associated with impaired healing and local administration of peroxisome proliferator-activated receptor (PPAR)γ agonists may modulate macrophage, improving healing. In this study, we investigated the effects of GQ-11, a partial/dual PPARα/γ agonist, on macrophage function and wound healing in diabetes. Wounds were surgically induced at the dorsum of C57BL/6J and BKS.Cg-Dock7 +/+ Lepr/J (db/db) mice and treated with hydrogel (vehicle), pioglitazone or GQ-11, for 7 or 10 days, respectively. After treatment, wounds were analyzed histologically and by quantitative PCR (qPCR). In addition, bone marrow-derived macrophages (BMDM) were cultured from C57BL/6J mice and treated with vehicle, pioglitazone, or GQ-11, after challenge with lipopolysaccharide or interleukin-4 to be analyzed by qPCR and flow cytometry. GQ-11 treatment upregulated anti-inflammatory/pro-healing factors and downregulated pro-inflammatory factors both in wounds of db/db mice and in BMDM. Wounds of db/db mice treated with GQ-11 exhibited faster wound closure and re-epithelization, increased collagen deposition, and less Mac-3 staining compared with vehicle, providing a new approach to treatment of diabetic wound healing to prevent complications. GQ-11 improves wound healing in db/db mice, regulating the expression of pro- and anti-inflammatory cytokines and wound growth factors, leading to increased re-epithelization and collagen deposition.
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http://dx.doi.org/10.1089/wound.2018.0911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703246PMC
September 2019

Anti-Trypanosoma cruzi effect of the photodynamic antiparasitic chemotherapy using phenothiazine derivatives as photosensitizers.

Lasers Med Sci 2020 Feb 12;35(1):79-85. Epub 2019 May 12.

Center of Biophotonics, School of Dentistry, Federal University of Bahia (UFBA), 62 Araujo Pinho Ave, Canela, Salvador, BA, 40110-150, Brazil.

Chagas disease is endemic in Latin America and increasingly found in non-endemic countries. Its treatment is limited due to the variable efficacy and several side effects of benznidazole. Photodynamic antimicrobial chemotherapy (PACT) may be an attractive approach for treating Chagas disease. Here, the trypanocidal activity of PACT was investigated in vitro using phenothiazine derivatives. The cytotoxicity of both, methylene blue (MB) and toluidine blue (TBO), was determined on macrophages cultures using AlamarBlue method. The trypanocidal activity of the two photosensitizers was initially evaluated by determining their IC values against trypomastigote forms. After this, the trypanocidal effect was evaluated in cultures of infected macrophages using an automatized image analysis protocol. All experiments were performed in the dark and in the clear phase (after a photodynamic exposure). The compounds showed no cytotoxicity in both phases at the tested concentrations. The IC values for the sole use of MB and TBO were 2.6 and 1.2 μM, respectively. The photoactivation of the compounds using a fixed energy density (J/cm) caused a reduction of the IC values to 1.0 and 0.9 μM, respectively. It was found that, on infected macrophage, the use of TBO significantly reduced the number of infected cells and parasitic load, and this effect was increased in the presence of light. The results of the present study are indicative that PACT may be considered as both selective and effective therapeutic intervention for treating Chagas disease.
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http://dx.doi.org/10.1007/s10103-019-02795-4DOI Listing
February 2020

Study of the in vitro metabolic profile of a new α-adrenergic agonist in rat and human liver microsomes by using liquid chromatography-multiple-stage mass spectrometry and nuclear magnetic resonance.

J Pharm Biomed Anal 2019 Aug 14;172:67-77. Epub 2019 Apr 14.

Núcleo de Pesquisa em Cromatografia (Separare), Department of Chemistry, Federal University of São Carlos, São Carlos, SP, 13565-905, Brazil. Electronic address:

A potent synthetic α-adrenergic agonist called PT-31, (3-(2-chloro-6-fluorobenzyl)-imidazolidine-2,4-dione), was recently detected as a potential drug to be used as an adjuvant drug to treat chronic pain. The excellent pharmacological property of PT-31 highlights the importance in elucidating its metabolism, which could provide valuable information about its metabolite profile for further pharmacokinetics studies and additionally to estimate the impact of its metabolites on the efficacy, safety and elimination of PT-31. In this work, the study of the in vitro metabolism of PT-31 was initially carried out by using a liquid chromatography coupled to ion trap multiple-stage mass spectrometer (LC-IT-MS) and a hybrid triple quadrupole/linear ion trap mass spectrometer (LC-QTrap). The production of at least three unknown oxidative metabolites was observed. Structural identification of the unknown metabolites was carried out by combination of LC-MS experiments, including selected reaction monitoring (SRM) and multi-stage full scan experiments. Further analysis of H-NMR led to the structural confirmation of the major metabolite. The results indicated that PT-31 was metabolized by a hydroxylation reaction in the imidazolidine-2,4-dione ring in rat and human liver microsomes, producing the metabolite 3-(2-chloro-6-fluorobenzyl)-5-hydroxyimidazolidine-2,4-dione in rat liver microsomes. A carbon hydroxylation onto the benzyl ring, produced two other minor metabolites of the PT-31 in rat liver microsomes.
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http://dx.doi.org/10.1016/j.jpba.2019.03.067DOI Listing
August 2019

CD4CD45RAFOXP3 Regulatory T Cells as Potential Biomarkers of Disease Activity in Systemic Lupus Erythematosus Brazilian Patients.

Biomed Res Int 2018 12;2018:3419565. Epub 2018 Jun 12.

Laboratório de Imunomodulação e Novas Abordagens Terapêuticas (LINAT), Núcleo de Pesquisa em Inovação Terapêutica Suely Galdino (NUPIT-SG), Universidade Federal de Pernambuco (UFPE), 50670-901, Brazil.

Heren, we analyzed Treg cells as potential biomarkers of disease activity in systemic lupus erythematosus (SLE) patients. Peripheral blood mononuclear cells from 30 SLE patients (15 active: SLEDAI > 6/15 SLE remission: SLEDAI< 6) and 15 healthy volunteers were purified. Treg immunophenotyping was performed using CD4, CD25, CD45, CD127, and FOXP3 markers. CD4FOXP3 Treg activation state was investigated based on CD45RA and FOXP3 expression. To increase the accuracy of our findings, a multivariate linear regression was performed. We showed a significant increase in the frequency of CD4FOXP3 Treg cells in SLE patients. However, unlike all other Treg cells phenotypes analyzed, only eTreg (CD4FOXP3CD45RA) (p=0.01) subtype was inversely correlated with disease activity while Foxp3nontreg (CD4FOXP3CD45RA) (p=0.003) exerted a direct influence in the outcome of the disease. Foxp3nontreg cells were the most consistent SLE active indicator, confirmed by multiple linear regression analyses. In summary, our results demonstrate Foxp3nontreg cells as new biomarkers in the search of an effective therapeutic strategy in SLE.
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http://dx.doi.org/10.1155/2018/3419565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020667PMC
January 2019

GQ-11: A new PPAR agonist improves obesity-induced metabolic alterations in LDLr mice.

Int J Obes (Lond) 2018 06 30;42(5):1062-1072. Epub 2018 Jan 30.

Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil.

Background: Obesity and insulin resistance/diabetes are important risk factors for cardiovascular diseases and demand safe and efficacious therapeutics.

Objective: To assess the effects of a new thiazolidine compound-GQ-11-on obesity and insulin resistance induced by a diabetogenic diet in LDL receptor-deficient (LDLr) mice.

Methods: Molecular docking simulations of GQ-11, PPARα and PPARγ structures were performed. Male C57BL/6J LDLr mice fed a diabetogenic diet for 24 weeks were treated with vehicle, GQ-11 or pioglitazone or (20 mg/kg/day) for 28 days by oral gavage. Glucose tolerance test, insulin, HOMA-IR, adipokines (leptin, adiponectin) and the lipid profile were assessed after treatment. Adipose tissue was analysed by X-ray analysis and morphometry; gene and protein expression were evaluated by real-time PCR and western blot, respectively.

Results: GQ-11 showed partial agonism to PPARγ and PPARα. In vivo, treatment with GQ-11 ameliorated insulin sensitivity and did not modify subcutaneous adipose tissue and body weight gain. In addition, GQ-11 restored adipokine imbalance induced by a diabetogenic diet and enhanced Glut-4 expression in the adipose tissue. Improved insulin sensitivity was also associated with lower levels of MCP-1 and higher levels of IL-10. Furthermore, GQ-11 reduced triglycerides and VLDL cholesterol and increased HDL-cholesterol by upregulation of Apoa1 and Abca1 gene expression in the liver.

Conclusion: GQ-11 is a partial/dual PPARα/γ agonist that demonstrates anti-diabetic effects. Additionally, it improves the lipid profile and ameliorates chronic inflammation associated with obesity in atherosclerosis-prone mice.
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http://dx.doi.org/10.1038/s41366-018-0011-7DOI Listing
June 2018

Solid dispersions to enhance the delivery of a potential drug candidate LPSF/FZ4 for the treatment of schistosomiasis.

Eur J Pharm Sci 2018 Mar 10;115:270-285. Epub 2018 Jan 10.

Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco, Rua Prof. Arthur de Sá, s/n, Cidade Universitária, 50740-52 Recife, PE, Brazil. Electronic address:

Drug candidate LPSF/FZ4 with promising schistosomicidal properties in vitro was previously synthesized. However, LPSF/FZ4 has limited aqueous solubility (<1 μg/mL), leading to ineffective dissolution and, therefore, no meaningful in vivo comparative studies could be pursued. This study was aimed to develop a proper amorphous solid dispersion (SD) to enhance the solubility and dissolution rate of LPSF/FZ4 such that its biological activity could be investigated. To better understand its physiological behavior, the pK of LPSF/FZ4, a monoprotic weak acid with NH group at the imidazolidine ring, was first determined to be 8.13 using an automated SiriusT3. The development of SD systems for LPSF/FZ4 involved the evaluation of various water-soluble polymer carriers such as PVP K-29/32, PVP K-90, HPMC K4M, PVPVA 64 and SOLUPLUS®. The most promising SD systems were selected through in vitro dissolution studies under nonsink conditions, together with physicochemical characterization as well as accelerated stability study. It was shown that SD of 10% LPSF/FZ4 in SOLUPLUS® and PVP K-90 could significantly increase the area-under-the-curve value of the nonsink dissolution profile (AUC values of the SD in SOLUPLUS® and PVP K-90 were 1381.03 and 1342.34 μL/mL·min, respectively, and that of the pure crystalline drug was 0.02 μL/mL·min), a useful surrogate for the in vivo bioavailability. Cmax values for the SD in SOLUPLUS® (12.50 μL/mL) and PVP K-90 (25.86 μL/mL) were also higher than the one of the crystalline drug (0.02 μL/mL). The SD system of LPSF/FZ4 in SOLUPLUS® showed a significant increase in schistosomicidal activity in an animal model as compared with the conventional treatment using crystalline drug, consistent with the AUC trend from the nonsink dissolution. Thus this SD system of LPSF/FZ4 could be useful as a potential formulation for treating schistosomiasis.
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http://dx.doi.org/10.1016/j.ejps.2018.01.014DOI Listing
March 2018

IL-17 and related cytokines involved in systemic sclerosis: Perspectives.

Autoimmunity 2018 02 19;51(1):1-9. Epub 2017 Dec 19.

b Laboratório de Imunomodulação e Novas Abordagens Terapêuticas Suely Galdino , Universidade Federal de Pernambuco , Recife , Brazil.

Systemic sclerosis (SSc) is a multisystemic, complex, and rare disease of connective tissue, with high morbidity and mortality, and without specific treatment. The disease is characterized by three main principles: vascular disease, autoantibody production and inflammation, and fibrosis. Since it is well defined that SSc is characterized by elevated production of TGF-β, IL-6, and IL-1, all of them cytokines related to Th17 differentiation, the hypothesis is that this disease may be strongly related to a polarization of the immune response towards the Th17 pathway. Considering the importance of a better understanding of the pathophysiology of Th17 pathway in SSc, this article aims to propose an update for a better understanding of current knowledge on main cytokines secreted by the Th17 cells (IL-17 A, IL-21, and IL-22) and the future prospects in the current disease.
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http://dx.doi.org/10.1080/08916934.2017.1416467DOI Listing
February 2018

Synthesis and Anticancer Evaluation of Thiazacridine Derivatives Reveals New Selective Molecules to Hematopoietic Neoplastic Cells.

Comb Chem High Throughput Screen 2017 ;20(8):713-718

Department of Biochemistry, Federal University of Pernambuco, Laboratory of Immunomodulation and New Therapeutic Approaches (LINAT), Recife, Brazil.

Aim And Objective: Cancer has become one of the leading causes of morbidity and mortality worldwide. Limitations associated with existing agents increase the need to develop more effective anticancer drugs to improve the therapeutic arsenal available. The aim of this study was to synthesize and evaluate the antiproliferative effects of three new thiazacridine derivatives.

Material And Methods: Using a three steps synthesis reaction, three novel thiazacridine derivatives were obtained and characterized: (Z)-5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-4-thioxo-thiazolidin- 2-one (LPSF/AC-99), (Z)-5-acridin-9-ylmethylene-3-(4-chloro-benzyl)-4-thioxo-thiazolidin-2- one (LPSF/AC-119) and (Z)-5-acridin-9-ylmethylene-3-(3-chloro-benzyl)-4-thioxo-thiazolidin-2- one (LPSF/AC-129). Toxicity and selectivity assays were performed by colorimetric assay. Then, changes in cell cycle and cell death induction mechanisms were assessed by flow cytometry.

Results: All compounds exhibited cytotoxicity to Raji (Burkitt's lymphoma) and Jurkat (acute T cell leukemia) cells, where LPSF/AC-119 showed best IC50 values (0.6 and 1.53 µ M, respectively). LPSF/AC-129 was the only cytotoxic compound in glioblastoma cell line NG97 (IC50 = 55.77 µ M). None of the compounds were toxic to normal human cells and induced neoplastic cell death primarily by apoptosis.

Conclusion: All derivatives were more cytotoxic to hematopoietic neoplastic cells when compared to solid tumor derived cells. All three compounds are promising for in vivo and combination therapy studies against cancer.
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http://dx.doi.org/10.2174/1386207320666170724114802DOI Listing
December 2018

GQ-16, a TZD-Derived Partial PPARγ Agonist, Induces the Expression of Thermogenesis-Related Genes in Brown Fat and Visceral White Fat and Decreases Visceral Adiposity in Obese and Hyperglycemic Mice.

PLoS One 2016 3;11(5):e0154310. Epub 2016 May 3.

Laboratório de Farmacologia Molecular, Faculdade de Ciências da Saúde, Universidade de Brasília, Brasília, Brazil.

Background: Beige adipocytes comprise a unique thermogenic cell type in the white adipose tissue (WAT) of rodents and humans, and play a critical role in energy homeostasis. In this scenario, recruitment of beige cells has been an important focus of interest for the development of novel therapeutic strategies to treat obesity. PPARγ activation by full agonists (thiazolidinediones, TZDs) drives the appearance of beige cells, a process so-called browning of WAT. However, this does not translate into increased energy expenditure, and TZDs are associated with weight gain. Partial PPARγ agonists, on the other hand, do not induce weight gain, but have not been shown to drive WAT browning. The present study was designed to investigate the effects of GQ-16 on BAT and on browning of WAT in obese mice.

Methods: Male Swiss mice with obesity and hyperglycemia induced by high fat diet were treated with vehicle, rosiglitazone (4 mg/kg/d) or the TZD-derived partial PPARγ agonist GQ-16 (40 mg/kg/d) for 14 days. Fasting blood glucose, aspartate aminotransferase, alanine aminotransferase and lipid profile were measured. WAT and brown adipose tissue (BAT) depots were excised for determination of adiposity, relative expression of Ucp-1, Cidea, Prdm16, Cd40 and Tmem26 by RT-qPCR, histological analysis, and UCP-1 protein expression analysis by immunohistochemistry. Liver samples were also removed for histological analysis and determination of hepatic triglyceride content.

Results: GQ-16 treatment reduced high fat diet-induced weight gain in mice despite increasing energy intake. This was accompanied by reduced epididymal fat mass, reduced liver triglyceride content, morphological signs of increased BAT activity, increased expression of thermogenesis-related genes in interscapular BAT and epididymal WAT, and increased UCP-1 protein expression in interscapular BAT and in epididymal and inguinal WAT.

Conclusion: This study suggests for the first time that a partial PPARγ agonist may increase BAT activity and induce the expression of thermogenesis-related genes in visceral WAT.

General Significance: These findings suggest that PPARγ activity might be modulated by partial agonists to induce WAT browning and treat obesity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0154310PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854408PMC
July 2017

New thiazolidinediones affect endothelial cell activation and angiogenesis.

Eur J Pharmacol 2016 Jul 21;782:98-106. Epub 2016 Apr 21.

Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil. Electronic address:

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor-γ (PPARγ) agonists used in treating type 2 diabetes that may exhibit beneficial pleiotropic effects on endothelial cells. In this study, we characterized the effects of three new TZDs [GQ-32 (3-biphenyl-4-ylmethyl-5-(4-nitro-benzylidene)-thiazolidine-2,4-dione), GQ-169 (5-(4-chloro-benzylidene)-3-(2,6-dichloro-benzyl)-thiazolidine-2,4-dione), and LYSO-7 (5-(5-bromo-1H-indol-3-ylmethylene)-3-(4-chlorobenzyl)-thiazolidine-2,4-dione)] on endothelial cells. The effects of the new TZDs were evaluated on the production of nitric oxide (NO) and reactive oxygen species (ROS), cell migration, tube formation and the gene expression of adhesion molecules and angiogenic mediators in human umbilical vein endothelial cells (HUVECs). PPARγ activation by new TZDs was addressed with a reporter gene assay. The three new TZDs activated PPARγ and suppressed the tumor necrosis factor α-induced expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. GQ-169 and LYSO-7 also inhibited the glucose-induced ROS production. Although NO production assessed with 4-amino-5-methylamino-2',7'-difluorofluorescein-FM probe indicated that all tested TZDs enhanced intracellular levels of NO, only LYSO-7 treatment significantly increased the release of NO from HUVEC measured by chemiluminescence analysis of culture media. Additionally, GQ-32 and GQ-169 induced endothelial cell migration and tube formation by the up-regulation of angiogenic molecules expression, such as vascular endothelial growth factor A and interleukin 8. GQ-169 also increased the mRNA levels of basic fibroblast growth factor, and GQ-32 enhanced transforming growth factor-β expression. Together, the results of this study reveal that these new TZDs act as partial agonists of PPARγ and modulate endothelial cell activation and endothelial dysfunction besides to stimulate migration and tube formation.
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http://dx.doi.org/10.1016/j.ejphar.2016.04.038DOI Listing
July 2016

New PPARγ partial agonist improves obesity-induced metabolic alterations and atherosclerosis in LDLr(-/-) mice.

Pharmacol Res 2016 Feb 17;104:49-60. Epub 2015 Dec 17.

Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil. Electronic address:

Peroxisome proliferator-activated receptor gamma (PPARγ) regulates multiple pathways involved in the pathogenesis of obesity and atherosclerosis. Here, we evaluated the therapeutic potential of GQ-177, a new thiazolidinedione, on diet-induced obesity and atherosclerosis. The intermolecular interaction between PPARγ and GQ-177 was examined by virtual docking and PPAR activation was determined by reporter gene assay identifying GQ-177 as a partial and selective PPARγ agonist. For the evaluation of biological activity of GQ-177, low-density lipoprotein receptor-deficient (LDLr(-/-)) C57/BL6 mice were fed either a high fat diabetogenic diet (diet-induced obesity), or a high fat atherogenic diet, and treated with vehicle, GQ-177 (20mg/kg/day), pioglitazone (20mg/kg/day, diet-induced obesity model) or rosiglitazone (15mg/kg/day, atherosclerosis model) for 28 days. In diet-induced obesity mice, GQ-177 improved insulin sensitivity and lipid profile, increased plasma adiponectin and GLUT4 mRNA in adipose tissue, without affecting body weight, food consumption, fat accumulation and bone density. Moreover, GQ-177 enhanced hepatic mRNA levels of proteins involved in lipid metabolism. In the atherosclerosis mice, GQ-177 inhibited atherosclerotic lesion progression, increased plasma HDL and mRNA levels of PPARγ and ATP-binding cassette A1 in atherosclerotic lesions. GQ-177 acts as a partial PPARγ agonist that improves obesity-associated insulin resistance and dyslipidemia with atheroprotective effects in LDLr(-/-) mice.
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http://dx.doi.org/10.1016/j.phrs.2015.12.010DOI Listing
February 2016

New indole-thiazolidine attenuates atherosclerosis in LDLr(-/-) mice.

Vascul Pharmacol 2015 Aug 11;71:174-80. Epub 2015 Apr 11.

Department of Clinical and Toxicological Analyses, Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, SP, Brazil. Electronic address:

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor γ (PPARγ) agonists that improve insulin-mediated glucose uptake and possess beneficial vasculoprotective actions. However, because undesirable side effects are associated with these drugs, novel TZDs are under development. In this study, we evaluated the biological activity of LYSO-7, a new indole-thiazolidine, on PPAR activation, inflammation and atherogenesis using a gene reporter assay, lipopolysaccharide (LPS)-activated RAW 264.7 cell culture, and a low-density lipoprotein receptor knockout (LDLr(-/-)) mouse model of atherosclerosis. LYSO-7 shows low cytotoxicity in RAW 264.7 cells and at 2.5μmol/L induces PPARα and PPARγ transactivation as well as inhibits LPS-induced nitrite production and the mRNA gene expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1). In addition, treatment with LYSO-7 reduces the development of atherosclerosis in LDLr(-/-) mice, improves the lipid profile, blood glucose levels, and downregulates CD40 and CD40L expression without affecting the body weight of the animals. Altogether, our data show that LYSO-7 possesses anti-inflammatory properties and that treatment with this TZD attenuates atherosclerosis progression in LDLr(-/-) mice by modulating lipid metabolism and inflammation. Thus, LYSO-7 shows potential as a new drug candidate for the treatment of atherosclerosis.
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http://dx.doi.org/10.1016/j.vph.2015.03.009DOI Listing
August 2015

Reduction of carrageenan-induced acute pulmonary inflammation in mice by novel thiazolidinedione derivative LPSF/RA-4.

Eur J Pharmacol 2013 Oct 12;718(1-3):197-205. Epub 2013 Sep 12.

Laboratório de Ultraestrutura, Instituto Aggeu Magalhães, FIOCRUZ, Recife, Brazil. Electronic address:

A number of studies have demonstrated the biological activities of peroxisome proliferator-activated receptors. However, few studies have addressed the effects of the agonists of these receptors on lung diseases. The aim of the present study was to evaluate the anti-inflammatory action of a novel synthetic thiazolidine derivative (5Z)-3-benzyl-5-(1H-indol-3-ylmethylene)-thiazolidine-2,4-dione (LPSF/RA-4) on acute lung inflammation (pleurisy) induced by carrageenan. Forty mice were randomly allocated to the following groups: (I) saline control group (sham); (II) carrageenan (CAR) group; (III) CAR+LPSF/RA-4 group treated with LPSF/RA-4 (60 μmol/kg); and (IV) INDO group treated with indometacin (5mg/kg). Total cell counts and the measure of nitric oxide (NO) were performed in pleural exudates. Lung fragments were processed for light microscopy, transmission electron microscopy, immunohistochemistry and Western blotting. The influx of leucocytes and NO levels were significantly reduced following treatment with LPSF/RA-4 and INDO. Histopathological and ultrastructural analyses of the CAR group revealed evident tissue alterations, such as oedema, infiltrates of inflammatory cells and emphysema. These alterations were significantly reduced in the groups treated with LPSF/RA-4 or INDO. Immunohistochemistry revealed an increase in inflammatory markers (COX-2, iNOS, TNF-α and IL-1β) in the lung tissue of the CAR group, whereas the groups treated with LPSF/RA-4 and INDO exhibited significant reductions in such immunomarkers. Western blot analysis revealed an increased expression of COX-2 and IL-1 in the CAR group, which was reduced by treatment with LPSF/RA-4. The present findings demonstrate the potent anti-inflammatory action of the novel derivative thiazolidinedione LPSF/RA-4 in acute lung injury induced by carrageenan.
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http://dx.doi.org/10.1016/j.ejphar.2013.08.033DOI Listing
October 2013

Dimethyl 2-[(acridin-9-yl)methyl-idene]malonate.

Acta Crystallogr Sect E Struct Rep Online 2013 Feb 12;69(Pt 2):o224. Epub 2013 Jan 12.

Laboratório de Imunopatologia Keizo Asami (LIKA), Departamento de Bioquímica, Universidade Federal de Pernambuco, 50670-901 Recife, PE, Brazil.

In the title compound, C(19)H(15)NO(4), the acridine system is essentially planar (r.m.s. deviation = 0.015 Å). The crystal packing exhibits π-π inter-actions between pairs of centrosymmetric mol-ecules, one of them between the central heterocyclic rings and others between the outer benzene rings of the acridine systems, with centroid-centroid distances of 3.692 (1) and 3.754 (1) Å, respectively. These pairs are further linked by additional π-π inter-actions along the a-axis direction through one of the two outer benzene ring of neighboring mol-ecules, with a centroid-centroid distance of 3.642 (2) Å.
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http://dx.doi.org/10.1107/S1600536813000500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569759PMC
February 2013

SAR, QSAR and docking of anticancer flavonoids and variants: a review.

Curr Top Med Chem 2012 ;12(24):2785-809

Federal University of Paraíba, Centre for Biotechnology, 50670-910, João Pessoa, PB, Brazil.

Flavonoids are phenolic compounds, secondary metabolites of plants that cause several benefits to our health, including helping the treatment against cancer. These pharmacological properties are associated with the ability of flavonoids in attenuating the generation of reactive oxygen species, acting as chelate compounds or affecting the oxi-redox cycle. In spite of the large number of information in term of SAR and QSAR, no recent review has tabulated and discussed in detail these data. In view of this, we bring here a detailed discussion of the structure-activity relationships (SAR) and quantitative structure-activity relationships (QSAR) models. We have also analyzed the correlation between the chemical structure of flavonoids and analogues to their anticancer activities. A large number of methodologies have been used to identify the characteristics of these compounds with their potential anticancer: multiple linear regression, principal components analysis, comparative molecular field analysis, comparative molecular similarity indices analysis, partial least squares, neural networks, configuration of classification and regression trees, Free-Wilson, docking; using topological, structural and enthalpies' descriptors. We also discussed the use of docking models, together with QSAR models, for the virtual screening of anticancer flavonoids. The importance of docking models to the medicinal chemistry of anticancer flavonoids has increased in the last decade, especially to help in identifying the structural determinants responsible for the activity. We tabulated here the most important examples of virtual screening determined for anticancer flavonoids and we highlighted the structural determinants. The mode of action, the most potent anticancer flavonoids and hints for the structural design of anticancer flavonoids are revised in details and provided here.
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http://dx.doi.org/10.2174/1568026611212240007DOI Listing
September 2013

Photodynamic antimicrobial chemotherapy (PACT) using phenothiazine derivatives as photosensitizers against Leishmania braziliensis.

Lasers Surg Med 2012 Dec 26;44(10):850-5. Epub 2012 Nov 26.

Center of Biophotonics, School of Dentistry, Federal University of Bahia (UFBA), 62 Araujo Pinho Ave, Canela, Salvador, BA 40110-150, Brazil.

Background And Objective: Cutaneous and mucocutaneous leishmaniasis are diseases characterized by skin or mucosal manifestations. In the new world, Leishmania braziliensis is the main etiological agent of cutaneous leishmaniasis, condition that may evolve to the mucocutaneous form. The therapeutic arsenal routinely employed to treat infected patients is unsatisfactory, especially for pentavalent antimonials, treatment recommended by the WHO, as they are often highly toxic, poorly tolerated and of variable effectiveness. This work aimed to evaluate in vitro the effectiveness of photodynamic antimicrobial chemotherapy as a new approach for the treatment of leishmaniasis.

Materials And Methods: A laser (λ = 660 nm, 40 mW, 4.2 J/cm2 , and 8.4 J/cm2 , CW) associated to phenothiazine's derivatives (5 and 10 µg/ml, toluidine blue O, methylene blue, or phenothiazine) on the promastigote forms of L. braziliensis in a single session. Samples were removed and analyzed in a hemocytometer 72 hours after PACT and viability of the parasites was assessed in quadruplicates.

Results: An important decrease in the number of viable parasites on all treated groups in comparison to their controls was observed as all tested compounds lead to significant parasite lethality being the highest lethality achieved with 10 µg/ml of TBO. No lethality was observed on groups treated with laser or with any of the compounds separately.

Conclusions: TBO presented higher parasite lethality in comparison to MB with impressive reduction from 1 hour to 5 minutes of pre-incubation time.
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http://dx.doi.org/10.1002/lsm.22099DOI Listing
December 2012

Enhanced antiproliferative activity of the new anticancer candidate LPSF/AC04 in cyclodextrin inclusion complexes encapsulated into liposomes.

AAPS PharmSciTech 2012 Dec 2;13(4):1355-66. Epub 2012 Oct 2.

Laboratório de Síntese e Vetorização de Moléculas, Universidade Estadual da Paraíba, João Pessoa, PB, Brazil.

LPSF/AC04 (5Z)-[5-acridin-9-ylmethylene-3-(4-methyl-benzyl)-thiazolidine-2,4-dione] is an acridine-based derivative, part of a series of new anticancer agents synthesized for the purpose of developing more effective and less toxic anticancer drugs. However, the use of LPSF/AC04 is limited due to its low solubility in aqueous solutions. To overcome this problem, we investigated the interaction of LPSF/AC04 with hydroxypropyl-β-cyclodextrin (HP-β-CyD) and hydroxypropyl-γ-cyclodextrin (HP-γ-CyD) in inclusion complexes and determine which of the complexes formed presents the most significant interactions. In this paper, we report the physical characterization of the LPSF/AC04-HP-CyD inclusion complexes by thermogravimetric analysis, differential scanning calorimetry, infrared spectroscopy absorption, Raman spectroscopy, (1)HNMR, scanning electron microscopy, and by molecular modeling approaches. In addition, we verified that HP-β-CyD complexation enhances the aqueous solubility of LPSF/AC04, and a significant increase in the antiproliferative activity of LPSF/AC04 against cell lines can be achieved by the encapsulation into liposomes. These findings showed that the nanoencapsulation of LPSF/AC04 and LPSF/AC04-HP-CyD inclusion complexes in liposomes leads to improved drug penetration into the cells and, as a result, an enhancement of cytotoxic activity. Further in vivo studies comparing free and encapsulated LPSF/AC04 will be undertaken to support this investigation.
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http://dx.doi.org/10.1208/s12249-012-9853-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513461PMC
December 2012

Preliminary antifungal and cytotoxic evaluation of synthetic cycloalkyl[b]thiophene derivatives with PLS-DA analysis.

Acta Pharm 2012 Jun;62(2):221-36

Departamento de Antibióticos, Universidade Federal de Pernambuco, Recife-PE, Brazil.

A series of 2-[(arylidene)amino]-cycloalkyl[b]thiophene-3-carbonitriles (2a-x) was synthesized by incorporation of substituted aromatic aldehydes in Gewald adducts (1a-c). The title compounds were screened for their antifungal activity against Candida krusei and Criptococcus neoformans and for their antiproliferative activity against a panel of 3 human cancer cell lines (HT29, NCI H-292 and HEP). For antiproliferative activity, the partial least squares (PLS) methodology was applied. Some of the prepared compounds exhibited promising antifungal and proliferative properties. The most active compounds for antifungal activity were cyclohexyl[b]thiophene derivatives, and for antiproliferative activity cycloheptyl[b]thiophene derivatives, especially 2-[(1H-indol-2-yl-methylidene)amino]- 5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbonitrile (2r), which inhibited more than 97 % growth of the three cell lines. The PLS discriminant analysis (PLS-DA) applied generated good exploratory and predictive results and showed that the descriptors having shape characteristics were strongly correlated with the biological data.
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http://dx.doi.org/10.2478/v10007-012-0017-yDOI Listing
June 2012

GQ-16, a novel peroxisome proliferator-activated receptor γ (PPARγ) ligand, promotes insulin sensitization without weight gain.

J Biol Chem 2012 Aug 14;287(33):28169-79. Epub 2012 May 14.

Laboratório de Farmacologia Molecular, Departamento de Ciências Farmacêuticas, Faculdade de Ciências da Saúde, Universidade de Brasília, 70919-970 Brazil.

The recent discovery that peroxisome proliferator-activated receptor γ (PPARγ) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-sensitizing agents. Herein we report the development of a novel thiazolidinedione that retains similar anti-diabetic efficacy as rosiglitazone in mice yet does not elicit weight gain or edema, common side effects associated with full PPARγ activation. Further characterization of this compound shows GQ-16 to be an effective inhibitor of Cdk5-mediated phosphorylation of PPARγ. The structure of GQ-16 bound to PPARγ demonstrates that the compound utilizes a binding mode distinct from other reported PPARγ ligands, although it does share some structural features with other partial agonists, such as MRL-24 and PA-082, that have similarly been reported to dissociate insulin sensitization from weight gain. Hydrogen/deuterium exchange studies reveal that GQ-16 strongly stabilizes the β-sheet region of the receptor, presumably explaining the compound's efficacy in inhibiting Cdk5-mediated phosphorylation of Ser-273. Molecular dynamics simulations suggest that the partial agonist activity of GQ-16 results from the compound's weak ability to stabilize helix 12 in its active conformation. Our results suggest that the emerging model, whereby "ideal" PPARγ-based therapeutics stabilize the β-sheet/Ser-273 region and inhibit Cdk5-mediated phosphorylation while minimally invoking adipogenesis and classical agonism, is indeed a valid framework to develop improved PPARγ modulators that retain antidiabetic actions while minimizing untoward effects.
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http://dx.doi.org/10.1074/jbc.M111.332106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3431672PMC
August 2012

2-Amino-4,5,6,7-tetra-hydro-benzo[b]thio-phene-3-carbonitrile.

Acta Crystallogr Sect E Struct Rep Online 2011 Dec 2;67(Pt 12):o3161. Epub 2011 Nov 2.

The title compound, C(9)H(10)N(2)S, was synthesized according to Gewald procedures by the reaction of cyclo-hexa-none with malonitrile and sulfur in the presence morpholine. The cyclo-hexane ring adopts a half-chair conformation and the thio-phene ring is essentially planar (r.m.s. deviation = 0.05 Å). The crystal packing is stabilized by two inter-molecular N-H⋯N hydrogen bonds, which link the mol-ecules into centrosymmetric rings with graph-set motif R(2) (2)(12).
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http://dx.doi.org/10.1107/S1600536811045338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238832PMC
December 2011

Solid dispersions of imidazolidinedione by PEG and PVP polymers with potential antischistosomal activities.

AAPS PharmSciTech 2011 Mar 1;12(1):401-10. Epub 2011 Mar 1.

Laboratório de Tecnologia dos Medicamentos, UFPE, Recife, Brazil.

Solid dispersions have been used as a strategy to improve the solubility, dissolution rate, and bioavailability of poor water-soluble drugs. The increase of the dissolution rate presented by (5Z)-3-(4-chloro-benzyl)-5-(4-nitro-benzylidene)-imidazolidine-2,4-dione (LPSF/FZ4) from the solid dispersions is related to the existence of intermolecular interactions of hydrogen bond type (>N-H···O<) between the amide group (>N-H) of the LPSF/FZ4 and the ether group (-O-) of the polyethyleneglycol polymer, or the carbonyl (C=O) of the polyvinylpyrrolidone polymer (PVP). The intensity of these interactions is directly reflected in the morphology acquired by LPSF/FZ4 in these systems, where a new solid phase, in the form of amorphous aggregates of irregular size, was identified through scanning electron microscopy and confirmed in the characterizations achieved using X-ray diffraction and thermal analysis of DSC. The solid dispersions with the polymer PVP, in higher concentrations, were revealed to be the best option to be used in the formulations of LPSF/FZ4 in both theoretical and experimental studies.
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http://dx.doi.org/10.1208/s12249-010-9556-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066376PMC
March 2011

Development and validation of an HPLC/MS/MS method for determining the thiazolidinone PG15 in rat plasma.

J AOAC Int 2010 Jul-Aug;93(4):1215-21

Universidade Federal de Pernambuco, Departamento de Antibi6ticos, Recife, Brazil.

A rapid, sensitive, and simple HPLC/MS/MS method was developed and validated for the determination of (5Z,E)-3-[2-(4-chlorophenyl)-2-oxoethyl]-5-(1H-indol-3-ylmethylene)-thiazolidine-2, 4-dione (PG15) in rat plasma using chlortalidone as an internal standard (IS). Analyses were performed using a C18 column and isocratic elution with acetonitrile-water (90 + 10, v/v) containing 10 mM ammonium hydroxide (pH 8.0) as the mobile phase pumped at 0.3 mL/min. Detection was performed by MS with negative ion mode electrospray ionization. Rat plasma samples were prepared by deproteinizing with acetonitrile. Detected fragments were 395.1 > 171.9 for PG15 and 337.3 > 189.9 for the IS. Calibration curves were linear from 10 to 1000 ng/mL, with the determination coefficient > 0.99. The intraday and interday precisions were less than 12.2 and 11.3%, respectively. The applicability of the HPLC/MS/MS method for pharmacokinetic studies was tested using plasma samples obtained after oral administration of PG15 to rats, and it provided the necessary sensitivity, linearity, precision, accuracy, and specificity.
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October 2010

Discovery of new inhibitors of Schistosoma mansoni PNP by pharmacophore-based virtual screening.

J Chem Inf Model 2010 Sep;50(9):1693-705

Laboratório de Química Medicinal e Computacional, Instituto de Física de São Carlos, Universidade de São Paulo, São Carlos-SP, Brazil.

Schistosomiasis is considered the second most important tropical parasitic disease, with severe socioeconomic consequences for millions of people worldwide. Schistosoma mansoni , one of the causative agents of human schistosomiasis, is unable to synthesize purine nucleotides de novo, which makes the enzymes of the purine salvage pathway important targets for antischistosomal drug development. In the present work, we describe the development of a pharmacophore model for ligands of S. mansoni purine nucleoside phosphorylase (SmPNP) as well as a pharmacophore-based virtual screening approach, which resulted in the identification of three thioxothiazolidinones (1-3) with substantial in vitro inhibitory activity against SmPNP. Synthesis, biochemical evaluation, and structure-activity relationship investigations led to the successful development of a small set of thioxothiazolidinone derivatives harboring a novel chemical scaffold as new competitive inhibitors of SmPNP at the low-micromolar range. Seven compounds were identified with IC(50) values below 100 μM. The most potent inhibitors 7, 10, and 17 with IC(50) of 2, 18, and 38 μM, respectively, could represent new potential lead compounds for further development of the therapy of schistosomiasis.
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http://dx.doi.org/10.1021/ci100128kDOI Listing
September 2010

Effect of chronic treatment with Rosiglitazone on Leydig cell steroidogenesis in rats: in vivo and ex vivo studies.

Reprod Biol Endocrinol 2010 Feb 9;8:13. Epub 2010 Feb 9.

Department of Morphology and Physiology, Universidade Federal Rural de Pernambuco, Recife, 52.171-900, Brazil.

Background: The present study was designed to examine the effect of chronic treatment with rosiglitazone - thiazolidinedione used in the treatment of type 2 diabetes mellitus for its insulin sensitizing effects - on the Leydig cell steroidogenic capacity and expression of the steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (P450scc) in normal adult rats.

Methods: Twelve adult male Wistar rats were treated with rosiglitazone (5 mg/kg) administered by gavage for 15 days. Twelve control animals were treated with the vehicle. The ability of rosiglitazone to directly affect the production of testosterone by Leydig cells ex vivo was evaluated using isolated Leydig cells from rosiglitazone-treated rats. Testosterone production was induced either by activators of the cAMP/PKA pathway (hCG and dbcAMP) or substrates of steroidogenesis [22(R)-hydroxy-cholesterol (22(R)-OH-C), which is a substrate for the P450scc enzyme, and pregnenolone, which is the product of the P450scc-catalyzed step]. Testosterone in plasma and in incubation medium was measured by radioimmunoassay. The StAR and P450scc expression was detected by immunocytochemistry.

Results: The levels of total circulating testosterone were not altered by rosiglitazone treatment. A decrease in basal or induced testosterone production occurred in the Leydig cells of rosiglitazone-treated rats. The ultrastructural and immunocytochemical analysis of Leydig cells from rosiglitazone-treated rats revealed cells with characteristics of increased activity as well as increased StAR and P450scc expression, which are key proteins in androgen biosynthesis. However, a number of rosiglitazone-treated cells exhibited significant mitochondrial damage.

Conclusion: The results revealed that the Leydig cells from rosiglitazone-treated rats showed significant reduction in testosterone production under basal, hCG/dbcAMP- or 22 (R)-OH-C/pregnenolone-induced conditions, although increased labeling of StAR and P450scc was detected in these cells by immunocytochemistry. The ultrastructural study suggested that the lower levels of testosterone produced by these cells could be due to mitochondrial damage induced by rosiglitazone.
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http://dx.doi.org/10.1186/1477-7827-8-13DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2829566PMC
February 2010

2-(2-Nitro-anilino)-4,5,6,7-tetra-hydro-benzo[b]thio-phene-3-carbonitrile.

Acta Crystallogr Sect E Struct Rep Online 2010 Sep 11;66(Pt 10):o2543. Epub 2010 Sep 11.

The title compound, C(15)H(13)N(3)O(2)S, was synthesized by the reaction of 2-amino-5,6,7,8-tetra-hydro-4H-cyclo-hepta-[b]thio-phene-3-carbonitrile and o-fluoro-nitro-benzene. The dihedral angle between the thio-phene and nitro-phenyl rings is 75.15 (2)°. In the crystal, inter-molecular N-H⋯N and C-H⋯O inter-actions lead to the formation of a supra-molecular chain extending along the c-axis direction.
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http://dx.doi.org/10.1107/S1600536810035439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2983395PMC
September 2010

2-(2-Nitro-anilino)-5,6,7,8-tetra-hydro-4H-cyclo-hepta-[b]thio-phene-3-carbonitrile.

Acta Crystallogr Sect E Struct Rep Online 2010 May 15;66(Pt 6):o1350-1. Epub 2010 May 15.

The title compound, C(16)H(15)N(3)O(2)S, was synthesized by the reaction of 2-amino-5,6,7,8-tetra-hydro-4H-cyclo-hepta-[b]thio-phene-3-carbonitrile and o-fluoro-nitro-benzene. The thio-phene and nitro-phenyl rings and amino and carbonitrile groups are coplanar with a maximum deviation of 0.046 (2) Å and a dihedral angle of 0.92 (6)° between the rings. The cyclo-hepta ring adopts a chair conformation. Intra-molecular N-H⋯O and C-H⋯S inter-actions occur. In the crystal, the mol-ecules form layers that are linked by π-π stacking inter-actions between the thio-phene and benzene rings [centroid-centroid distances = 3.7089 (12) and 3.6170 (12) Å].
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http://dx.doi.org/10.1107/S1600536810017149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2979624PMC
May 2010

Interaction of morphine with a new alpha2-adrenoceptor agonist in mice.

J Pain 2010 Jan 22;11(1):71-8. Epub 2009 Oct 22.

Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Brazil.

Unlabelled: Finding new chemicals or adjuvants with analgesic effects in the central nervous system is clinically relevant due to the limited number of drugs with these properties. Here, we present PT-31, which is chemically related to 3-benzyl-imidazolidine, with an analgesic profile that results from alpha(2)-adrenoceptor activation. Intraperitoneal administration of PT-31 dose-dependently produced antinociception in the hot plate test, and interacted synergistically with morphine. This effect was completely reversed by yohimbine, a non-selective antagonist of alpha(2)-adrenoceptors, and by BRL 44408, a selective alpha(2A)-adrenoceptor antagonist. The combination of morphine and PT-31 produced greater antinociceptive activity than either alone, and isobolographic analysis revealed a synergistic interaction between these compounds. Docking results confirm the high affinity of the PT-31 ligand at the alpha(2A)-adrenoceptor.

Perspective: This study introduces a new analgesic compound (PT-31) that acts via alpha(2A)-adrenoceptor activation. A significant increase in analgesia was observed when co-administered with morphine. PT-31 is an interesting new substance for pain therapy.
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http://dx.doi.org/10.1016/j.jpain.2009.08.001DOI Listing
January 2010

A theoretical study of red-shifting and blue-shifting hydrogen bonds occurring between imidazolidine derivatives and PEG/PVP polymers.

J Mol Model 2010 Jan 12;16(1):119-27. Epub 2009 Jun 12.

Departamento de Ciências Farmacêuticas, Universidade Federal de Pernambuco, 50740-521 Recife, PE, Brazil.

A theoretical study is presented with the aim to investigate the molecular properties of intermolecular complexes formed by the monomeric units of polyvinylpyrrolidone (PVP) or polyethyleneglycol (PEG) polymers and a set of four imidazolidine (hydantoine) derivatives. The substitution of the carbonyl groups for thiocarbonyl in the hydantoin scaffold was taken into account when analyzing the effect of the hydrogen bonds on imidazolidine derivatives. B3LYP/6-31G(d,p) calculations and topological integrations derived from the quantum theory of atoms in molecules (QTAIM) were applied with the purpose of examining the N-H···O hydrogen bond strengths formed between the amide group of the hydantoine ring and the oxygen atoms of PVP and PEG polymers. The effects caused by the N-H···O interaction fit the typical evidence for hydrogen bonds, which includes a variation in the stretch frequencies of the N-H bonds. These frequencies were identified as being vibrational red-shifts because their values decreased. Although the values of such calculated interaction energies are between 12 and 33 kJ mol(-1), secondary intermolecular interactions were also identified. One of these secondary interactions is formed through the interaction of the benzyl hydrogen atoms with the oxygen atoms of the PVP and PEG structures. As such, we have analyzed the stretch frequencies on the C-H bonds of the benzyl groups, and blue-shifts were identified on these bonds. In this sense, the intermolecular systems formed by hydantoine derivatives and PVP/PEG monomers were characterized as a mix of red-shifting and blue-shifting hydrogen-bonded complexes.
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http://dx.doi.org/10.1007/s00894-009-0525-yDOI Listing
January 2010
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