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- ItemAcesso aberto (Open Access)Biological and conformational evaluation of angiotensin II lactam bridge containing analogues(Elsevier B.V., 2011-12-10) Oliveira Junior, Vani Xavier; Fázio, Marcos Antonio [UNIFESP]; Silva, Adriana Farias; Campana, Patricia Targon; Pesquero, João Bosco [UNIFESP]; Santos, Edson Lucas; Costa-Neto, Cláudio Miguel; Miranda, Antonio [UNIFESP]; Universidade Federal do ABC (UFABC); Universidade Federal de São Paulo (UNIFESP); Universidade de São Paulo (USP); Fundacao Univ Fed Grande DouradosAngiotensin II (All) is the active octapeptide product of the renin enzymatic cascade, which is responsible for sustaining blood pressure. in an attempt to establish the All-receptor-bound conformation of this octapeptide, we designed conformationally constrained analogues by scanning the entire All sequence with an i-(i+2) and i-(i + 3) lactam bridge consisting of an Asp-(Xaa)(n)-Lys scaffold. Most analogues presented low agonistic activity when compared to All in the different bioassays tested. the exceptions are cyclo(0-1a) [Asp(0), endo-(Lys(1a))]-All (1) and [Asp(0), endo-(Lys(1a))]-All (2), both of which showed activity similar to All. Based on peptide 1 and the analogue cyclo(3-5)[Sar(1), Asp(3), Lys(5)]-All characterized by Matsoukas et al., we analyzed the agonistic and antagonistic activities, respectively, through a new monocyclic peptide series synthesized by using the following combinations of residues as bridgehead elements for the lactam bond formation: D- or L-Asp combined with D- or L-Lys or L-Glu combined with L-Orn. Six analogues showed an approximately 20% increase in biological activity when compared with peptide (1) and were equipotent to All. in contrast, six analogues presented antagonistic activity. These results suggest that the position of the lactam bridge is more important than the bridge length or chirality for recognition of and binding to the angiotensin 11 AT1-receptor. (C) 2011 Elsevier B.V. All rights reserved.
- ItemAcesso aberto (Open Access)Compostos guanidínicos e 2-aminotiazólicos: explorando fontes naturais e sintéticas na busca de novos fármacos leishmanicidas(Universidade Federal de São Paulo, 2019) Amorim, Carina Rodrigues [UNIFESP]; Rando, Daniela Gonçales Galasse [UNIFESP]; Lago, João Henrique Ghilardi [UNIFESP]; http://lattes.cnpq.br/2325513222088331; http://lattes.cnpq.br/0444555512774012; http://lattes.cnpq.br/8324304221750007A leishmaniose é considerada uma doença negligenciada. As doenças negligenciadas são um grupo diverso de doenças causadas por agentes infecciosos e parasitários, com prevalência em 149 países tropicais e subtropicais, afetando mais de um bilhão de pessoas. As terapias disponíveis para o tratamento das leishmanioses estão longe de serem satisfatórias, pois os fármacos existentes no mercado hoje em dia são caros, além de possuírem elevada toxicidade, eficácia limitada e presença de resistência frente a estes parasitas. Este trabalho tem como objetivo a busca de novas moléculas ativas contra os parasitas causadores das leishmanioses por meio da obtenção de uma biblioteca composta por um derivado guanidínico obtido por extração da espécie vegetal Alchornea glandulosa e por compostos sintéticos derivados de 4-fenil-2- aminotiazólicos. Através da extração das folhas da A. glandulosa, foi obtido o alcaloide guanidínico alchornedina, isolado e caracterizado por espectros de RMN de 1H, RMN de 13C e espectros de massas. O alcaloide guanidínico alchornedina foi submetido a testes biológicos contra a forma promastigota de Leishmania amazonensis o qual foi inativo, porém apresentou atividade moderada contra a forma promastigota de Leishmania infantum com IC50 31,8 μM, mas não se mostrou ativo contra a forma amastigota. O índice de seletividade (IS) foi de 6,29 semelhante ao fármaco padrão do ensaio, a miltefosina 7,44. Quanto aos compostos sintéticos 25 compostos derivados de 4-fenil-2-aminotiazois foram obtidos, os quais se classificam em 4 séries com 17 compostos finais e oito compostos intermediários, estes foram obtidos, purificados e analisados biologicamente contra L. amazonensis. O composto 1-E apresentou maior atividade biológica com IC50 de 2,44 µM e IS igual a 96, com comportamento semelhante à pentamidina (IC50 = 2,29 µM), seguidos dos compostos 1-A (IC50 de 4,74 µM e IS de 18) e 1-D (IC50 de 5,50 µM e IS 06). Os três melhores compostos foram da série 1, ou seja, derivados do 5-nitro-2- tiofenocarboxaldeído.
- ItemSomente MetadadadosGibbilimbol analogues as antiparasitic agents-Synthesis and biological activity against Trypanosoma cruzi and Leishmania (L.) infantum(Pergamon-Elsevier Science Ltd, 2016) Varela, Marina T. [UNIFESP]; Dias, Roberto Z. [UNIFESP]; Martins, Ligia F.; Ferreira, Daiane D.; Tempone, Andre G.; Ueno, Anderson K. [UNIFESP]; Lago, Joao Henrique G. [UNIFESP]; Fernandes, Joao Paulo S. [UNIFESP]The essential oils from leaves of Piper malacophyllum (Piperaceae) showed to be mainly composed by two alkenylphenol derivatives: gibbilimbols A and B. After isolation and structural characterization by NMR and MS data analysis, both compounds were evaluated against promastigote/amastigote forms of Leishmania (L.) infantum as well as trypomastigote/amastigote forms of Trypanosoma cruzi. The obtained results indicated that gibbilimbol B displayed potential against the tested parasites and low toxicity to mammalian cells, stimulating the preparation of several quite simple synthetic analogues in order to improve its activity and to explore the preliminary structure-activity relationships (SAR) data. Among the prepared derivatives, compound LINS03003 (n-octyl-4-hydroxybenzylamine) displayed the most potent IC50 values of 5.5 and 1.8 mu M against amastigotes of T. cruzi and L. (L.) infantum, respectively, indicating higher activity than the natural prototype. In addition, this compound showed remarkable selectivity index (SI) towards the intracellular forms of Leishmania (SI = 13.1) and T. cruzi (SI = 4.3). Therefore, this work indicated that preparation of synthetic compounds structurally based in the bioactive natural products could be an interesting source of novel and selective compounds against these protozoan parasites. (C) 2016 Elsevier Ltd. All rights reserved.
- ItemSomente MetadadadosHighly Potential Antiplasmodial Restricted Peptides(Wiley-Blackwell, 2015-02-01) Der Torossian, Torres Marcelo; Silva, Adriana F.; Alves, Flavio L. [UNIFESP]; Capurro, Margareth L.; Miranda, Antonio [UNIFESP]; Xavier, Oliveira Vani; Universidade Federal do ABC (UFABC); Universidade Federal de São Paulo (UNIFESP); Universidade de São Paulo (USP)Malaria is an infectious disease responsible for approximately one million deaths annually. the antimalarial effects of angiotensin II and its analogs against Plasmodium gallinaceum and P.falciparum have recently been reported. To evaluate antiplasmodial activity, we synthesized five angiotensin II-restricted analogs containing disulfide bridges. To accomplish this, peptides containing two inserted amino acid residues (cysteine) were synthesized by the Fmoc solid-phase method, purified by liquid chromatography, and characterized by mass spectrometry. Conformational studies were performed by circular dichroism. the results indicated that two of the analogs had higher antiplasmodium activity (92% and 98% activity) than angiotensin II (88% activity), measured by fluorescence microscopy. Results showed that the insertion position must be selected, to preserve the hydrophobic interactions between the non-polar residues, as this affects antiplasmodial activity. the circular dichroism studies suggested that the active analogs as well as the native angiotensin II adopt a -turn conformation in different solutions. This approach provided insight for understanding the effects of restricting the ring size and position on the bioactivity of angiotensin II and provides a new direction for the design of potential chemotherapeutic agents.
- ItemSomente MetadadadosThe Importance of Ring Size and Position for the Antiplasmodial Activity of Angiotensin II Restricted Analogs(Springer, 2014-09-01) Torres, Marcelo Der Torossian; Silva, Adriana Farias; Alves, Flavio Lopes [UNIFESP]; Capurro, Margareth Lara [UNIFESP]; Miranda, Antonio [UNIFESP]; Oliveira Junior, Vani Xavier; Universidade Federal do ABC (UFABC); Universidade Federal de São Paulo (UNIFESP)Malaria is caused by the protozoa Plasmodium and is responsible for approximately one million deaths annually. the antimalarial effects of angiotensin II and its analogs against Plasmodium gallinaceum and falciparum have recently been reported. Here, 12 angiotensin II restricted analogs that contain i - (i + 2), i - (i + 3) and i - (i + 4) lactam bridges were synthesized to analyze their effect on antiplasmodial activity. To accomplish this, peptides containing two amino acid residues (aspartic or glutamic acids and lysine or ornithine), were synthesized by the t-Boc solid phase method, purified by liquid chromatography, and characterized by mass spectrometry, and conformational studies were performed by circular dichroism. the results indicate that some of the analogs had anti-plasmodium activity similar to angiotensin II (88 % activity). Among those, eight compounds exhibited high activity (> 70 %), measured by fluorescence microscopy. the analogs with smaller lactam rings and an aspartic acid residue as the bridgehead element had lower levels of lytic activity. the results obtained with the new restricted analogs showed that the insertion position (near the N-terminus), the ring size, and the number of residues between the rings are as important as the components of lactam bridge, regardless of their chirality. the circular dichroism studies suggest that the active analogs, and native angiotensin II, adopt a beta-fold conformation in different solutions. in conclusion, this approach provides insight for understanding the effects of restricting the ring size and position on the bioactivity of angiotensin II and provides a new direction for the design of potential chemotherapeutic agents.
- ItemAcesso aberto (Open Access)Metabólitos especiais dos galhos de Nectandra leucantha Nees & Mart. (LAURACEAE) e derivados semissintéticos – caracterização molecular, avaliação do potencial e mecanismo antitumoral contra o melanoma murino(Universidade Federal de São Paulo, 2018-03-16) Sousa, Fernanda Samara de [UNIFESP]; Lago, João Henrique Ghilardi [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)In this work, extracts from twigs of Nectandra leucantha (Lauraceae) displayed in vitro cytotoxic activity against murine melanoma tumorigenic cell line (B16F10). Thus, hexane extract of N. leucantha was subjected to chromatographic fractionation, which allowed the isolation of six neolignans: 1,2-dimethoxy-6-[2'-methoxy-4'-(8'-propenyl) phenoxy] -4-(8-propenyl) benzene (I), dehydrodieugenol B (II), 1,2-dimethoxy-6- [2'-methoxy-4 '- (8'-propenyl) phenoxy]-4-(7-hydroxy-8-propenyl) benzene (III), 1-hydroxy-2-methoxy-6- [2'-methoxy-4 '-(8'-propenyl) phenoxy]-4-(7- propenyl) benzene (IV), 1,2-dimethoxy-6- [2'-methoxy-4 '-(8'-propenyl) phenoxy]-4-(7-oxo-8-propenyl) benzene (V) and 2-methoxy-6-[2'-methoxy-4'-(8'-propenyl) phenoxy]-4-(7-oxo-8-propenyl) benzene (VI), of which V and VI are unpublished in the literature. Structures of substances I - VI were defined by spectroscopic and spectrometric methods. These compounds were evaluated for their cytotoxicity against SK-BR-3, HCT, U87-MG, A2058 and B16F10 tumorigenic lines. Among the compounds tested, the most active were II and VI, presenting IC50 values of 78.8 ± 2.8 and 82.2 ± 3.5 μM against B16F10, respectively. The mechanism of action of compounds II and VI against murine melanoma cell line showed both compounds can induce intrinsic apoptosis. Compound II induced caspase-3 and PARP activation, while compound VI acted deregulating Bcl-2 protein levels. These effects were accompanied by increased levels of reactive oxygen species, as a consequence of mitochondrial damage, followed by F-actin aggregation in the death process of these cells. In addition, compound II displayed oxidative properties, and both compounds, especially VI, displayed potential to alkylate nucleophiles, suggesting an accessory mechanism of cytotoxicity induction, by these metabolites. For structure-activity relationship (SAR) studies, 24 semisynthetic derivatives were prepared from I and II, and their respective IC50 values were also determined against B16F10. Derivatives 2a (2-methoxy-6-(2-methoxy-4-propylphenoxy)-4-propylphenol), 2h (2-methoxy-6-(2-methoxy-4-propylphenoxy)-4-propylphenyl acetate) and 3h (5-(cyclopropylmethyl)-1-(4-(cyclopropylmethyl)-2-methoxyphenoxy)-2,3-dimethoxybenzene) were the most active compounds, presenting IC50 values of 53.3 ± 2.4, 51.8 ± 1.6 and 59.3 ± 3.2 μM, respectively, suggesting that the hydrogenation (2a), hydrogenation/acetylation (2h) and epoxidation (3h) cause an increase in the antitumor potential of natural products I and II. The 4-OAc, 4-OH and 1-bezyloxirane groups of the tested structures were chosen as the most important, by their statistical impact at cytotoxicity. For the selected position, bioisosteres substituents were applied. The results suggested that, some projected neolignans by prediction methods achieved lower IC50 than semi-synthetic derivatives, pointing them as promising candidates for synthesis.
- ItemSomente MetadadadosNatural polyprenylated benzophenones inhibiting cysteine and serine proteases(Elsevier B.V., 2009-03-01) Martins, Felipe T.; Assis, Diego M.; Santos, Marcelo H. dos; Camps, I.; Veloso, Marcia P.; Juliano, Maria A. [UNIFESP]; Alves, Lira C.; Doriguetto, Antonio C.; Univ Fed Alfenas; Universidade Federal de São Paulo (UNIFESP)We have investigated the in vitro inhibition of papain, trypsin, and cathepsins B and G by five benzophenone-type compounds, three natural ones isolated from Garcinia brasiliensis and two synthetic derivatives. the activities of pentaprenylated trihydroxy-substituted benzophenone guttiferone A (1) on all assayed enzymes were approximately 2-69 folds higher than that manifested by mono-hydroxylated tetraprenylated and triprenylated compounds epiclusianone (2) and garciniaphenone (3), respectively, the other natural benzophenones that also inhibited significantly the four enzymes. Differently, the synthetic derivatives 2,2',4-trihydroxybenzophenone (4) and diphenylmethanone (5) have inhibited weakly the studied proteases. Furthermore, compound 1 has bonded preferentially to cathepsin G, once its IC(50) value (2.7 +/- 0.1 mu M) on such peptidase is quite similar to that of the classical inhibitor of serine proteases, chymostatin (2.1 +/- 0.1 mu M). Interesting structure-activity relationships (SARs) were confirmed by flexible docking simulations, likewise the potential usefulness of natural compound 1 as antitumoral drug is strengthened by our results concerning the antiproteolytic activity. (C) 2008 Elsevier Masson SAS. All rights reserved.
- ItemSomente MetadadadosNew alkenyl derivative from Piper malacophyllum and analogues: Antiparasitic activity against Trypanosoma cruzi and Leishmania infantum(Wiley, 2017) Varela, Marina T. [UNIFESP]; Lima, Marta L.; Galuppo, Mariana K.; Tempone, Andre G.; de Oliveira, Alberto; Lago, Joao Henrique G.; Fernandes, Joao Paulo S. [UNIFESP]Alkylphenols isolated from Piper malacophyllum (Piperaceae), gibbilimbols A and B, showed interesting activity against the parasites Trypanosoma cruzi and Leishmania infantum. In continuation to our previous work, a new natural product from the essential oil of the leaves of P.malacophyllum was isolated, the 5-[(3E)-oct-3-en-1-il]-1,3-benzodioxole, and also a new set of five compounds was prepared. The antiparasitic activity of the natural product was evaluated in vitro against these parasites, indicating potential against the promastigote/trypomastigote/amastigote forms (IC50 32-83m) of the parasites and low toxicity (CC50>200m) to mammalian cells. The results obtained to the synthetic compounds indicated that the new derivatives maintained the promising antiparasitic activity, but the cytotoxicity was considerably lowered. The amine derivative LINS03011 displayed the most potent IC50 values (13.3 and 16.7m) against amastigotes of T.cruzi and L.infantum, respectively, indicating comparable activity to the phenolic prototype LINS03003, with threefold decreased (CC50 73.5m) cytotoxicity, leading the selectivity index (SI) towards the parasites up to 24.5. In counterpart, LINS03011 has not shown membrane disruptor activity in SYTOX Green model. In summary, this new set showed the hydroxyl is not essential for the antiparasitic activity, and its substitution could decrease the toxicity to mammalian cells.
- ItemAcesso aberto (Open Access)Pharmacological Characterization of 5-Substituted 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines: Novel Antagonists for the Histamine H-3 and H-4 Receptors with Anti-inflammatory Potential(Frontiers Media Sa, 2017) Correa, Michelle F. [UNIFESP]; Barbosa, Alefe J. R. [UNIFESP]; Teixeira, Larissa B.; Duarte, Diego A.; Simoes, Sarah C.; Parreiras-e-Silva, Lucas T.; Balbino, Aleksandro M. [UNIFESP]; Landgraf, Richardt G. [UNIFESP]; Bouvier, Michel; Costa-Neto, Claudio M.; Fernandes, Joao P. S. [UNIFESP]The histamine receptors (HRs) are traditional G protein-coupled receptors of extensive therapeutic interest. Recently, H3R and H4R subtypes have been targeted in drug discovery projects for inflammation, asthma, pain, cancer, Parkinson's, and Alzheimer's diseases, which includes searches for dual acting H3R/H4R ligands. In the present work, nine 1-[(2,3-dihydro-1-benzofuran-2-yl) methyl] piperazine (LINS01 series) molecules were synthesized and evaluated as H3R and H4R ligands. Our data show that the N-allyl-substituted compound LINS01004 bears the highest affinity for H3R (pK(i) 6.40), while the chlorinated compound LINS01007 has moderate affinity for H4R (pK(i) 6.06). In addition, BRET assays to assess the functional activity of G(i)1 coupling indicate that all compounds have no intrinsic activity and act as antagonists of these receptors. Drug-likeness assessment indicated these molecules are promising leads for further improvements. In vivo evaluation of compounds LINS01005 and LINS01007 in a mouse model of asthma showed a better anti-inflammatory activity of LINS01007 (3 g/kg) than the previously tested compound LINS01005. This is the first report with functional data of these compounds in HRs, and our results also show the potential of their applications as anti-inflammatory.