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1.
Curr Mol Pharmacol ; 11(3): 226-236, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29676239

RESUMO

BACKGROUND: The Renin Angiotensin System (RAS) is pharmacologically targeted to reduce blood pressure, and patient compliance to oral medications is a clinical issue. The mechanisms of action of angiotensin receptor blockers (ARBs) in reducing blood pressure are not well understood and are purported to be via a reduction of angiotensin II signaling. OBJECTIVE: We aimed to develop a transdermal delivery method for ARBs (losartan potassium and valsartan) and to determine if ARBs reveal a vasodilatory effect of the novel RAS peptide, alamandine. In addition, we determined the anti-hypertensive effects of the transdermal delivery patch. METHODS: In vitro and in vivo experiments were performed to develop an appropriate therapeutic system, promising an alternative and more effective therapy in the treatment of hypertension. A variety of penetration enhancers were selected such as isopropyl myristate, propylene glycol, transcutol and dimenthyl sulfoxide to obtain a constant release of drugs through human skin. Small resistance vessels (kidney interlobar arteries) were mounted in organ baths and incubated with an ARB. Vasodilatory curves to alamandine were constructed. RESULTS: The in vivo studies demonstrate that systemic absorption of valsartan and losartan potassium using the appropriate formulations provide a steady state release and anti-hypertensive effect even after 24 hours of transdermal administration. No apparent skin irritations (erythema, edema) were observed with the tested formulations. We also show that blocking the AT1 receptor of rabbit interlobar arteries in vitro reveals a vasodilatory effect of alamandine. CONCLUSION: This study reveals the potential mechanism of AT1 receptor blockade via alamandine, and is an important contribution in developing a favorable, convenient and painless antihypertensive therapy of prolonged duration through transdermal delivery of AT1 blockers.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Vasos Sanguíneos/fisiologia , Rim/irrigação sanguínea , Receptor Tipo 1 de Angiotensina/metabolismo , Vasodilatação/efeitos dos fármacos , Administração Cutânea , Angiotensina II/farmacologia , Animais , Vasos Sanguíneos/efeitos dos fármacos , Humanos , Losartan/farmacologia , Masculino , Oligopeptídeos/farmacologia , Coelhos , Ratos Wistar , Reprodutibilidade dos Testes , Absorção Cutânea/efeitos dos fármacos , Valsartana/farmacologia
2.
Comb Chem High Throughput Screen ; 17(8): 652-62, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24875271

RESUMO

The dissolution of the antihypertensive AT1 antagonist olmesartan in methanol generates in situ a new highly bioactive methyl ether analogue via SN1 mechanism involving an intramolecular proton transfer from carboxyl to hydroxyl group. Theoretical calculations confirmed the thermodynamic control preference of methyl ether versus the antagonistic product methyl ester. Α facile synthetic method for olmesartan methyl ether from olmesartan or olmesartan medoxomil is also described. Interestingly, the introduction of the methyl group to olmesartan did not alter its pharmacological properties. This observation opens new avenues in the synthesis of novel drugs, since hydroxyl and carboxylate groups have an orthogonal relationship in many drugs.


Assuntos
Antagonistas de Receptores de Angiotensina/química , Imidazóis/química , Tetrazóis/química , Antagonistas de Receptores de Angiotensina/síntese química , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Imidazóis/síntese química , Modelos Teóricos , Estrutura Molecular , Tetrazóis/síntese química
3.
J Chem Inf Model ; 53(11): 2798-811, 2013 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-24053563

RESUMO

This study investigates the binding of angiotensin II (AngII) to the angiotensin II type 1 receptor (AT1R), taking into consideration several known activation elements that have been observed for G-protein-coupled receptors (GPCRs). In order to determine the crucial interactions of AngII upon binding, several MD simulations were implemented using AngII conformations derived from experimental data (NMR ROEs) and in silico flexible docking methodologies. An additional goal was to simulate the induced activation mechanism and examine the already known structural rearrangements of GPCRs upon activation. Performing MD simulations to the AT1R - AngII - lipids complex, a series of dynamic changes in the topology of AngII and the intracellular part of the receptor were observed. Overall, the present study proposes a complete binding profile of AngII to the AT1R, as well as the key transitional elements of the receptor and the agonist peptide upon activation through NMR and in silico studies.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Angiotensina II/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Receptor Tipo 1 de Angiotensina/química , Ácido Acético/química , Sítios de Ligação , Dimetil Sulfóxido/química , Humanos , Ligantes , Espectroscopia de Ressonância Magnética , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Receptores CXCR4/química , Homologia Estrutural de Proteína , Termodinâmica , Ácido Trifluoracético/química
4.
Expert Opin Ther Pat ; 23(11): 1483-94, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23968548

RESUMO

INTRODUCTION: For two decades a class of pharmaceutical molecules with proved beneficial therapeutic properties, especially in hypertension, has been introduced in the market aiming to specifically prevent the detrimental effects of the peptide hormone Angiotensin II at the AT1 receptor. The prototype of this class was losartan and based on its structure, several drugs were launched and also called 'Sartans'. New structural features on these molecules can provide multi-target properties in the RAS or other systems. New methodologies were developed for the treatment of hypertension utilizing either AT1 antagonists alone or as cocktails. AREAS COVERED: In this review article, authors aim to cover information provided by patents of the years 2008 - 2012. The rationale of writing this review article is to cover the most important patents which can forward the field with new important discoveries. EXPERT OPINION: From the patent investigation it is clear that new areas on the subject are still offered for new discoveries. New structural features can be still considered in the synthetic compounds that can advance the knowledge and beneficial effects on diseases related to Angiotensin II and AT1 receptor. There is era also for new formulations (i.e., cyclodextrins, polymers and liposomes). The multitarget approach can be further strengthened and more combinations can be sought in the rational drug design for seeking cocktails. Furthermore, the revealing of the complexity of the RAS offers new avenues for novel targets and this must not be overlooked.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Química Farmacêutica , Combinação de Medicamentos , Descoberta de Drogas , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Modelos Moleculares , Oxazóis/farmacologia , Patentes como Assunto , Sistema Renina-Angiotensina/efeitos dos fármacos , Relação Estrutura-Atividade
5.
Molecules ; 18(7): 7510-32, 2013 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-23807577

RESUMO

In the present work, a facile and efficient route for the synthesis of a series of N-substituted imidazole derivatives is described. Docking studies have revealed that N-substituted imidazole derivatives based on (E)-urocanic acid may be potential antihypertensive leads. Therefore, new AT1 receptor blockers bearing either the benzyl or the biphenylmethyl moiety at the N-1 or N-3 position, either the (E)-acrylate or the propanoate fragment and their related acids at the C-4 position as well as a halogen atom at the C-5 position of the imidazole ring, were synthesized. The newly synthesized analogues were evaluated for binding to human AT1 receptor. The biological results showed that this class of molecules possesses moderate or no activity, thus not always confirming high docking scores. Nonetheless, important conclusions can be derived for their molecular basis of their mode of action and help medicinal chemists to design and synthesize more potent ones. An aliphatic group as in losartan seems to be important for enhancing binding affinity and activity.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacologia , Imidazóis/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Anti-Hipertensivos/química , Desenho de Fármacos , Humanos , Imidazóis/síntese química , Imidazóis/química , Simulação de Acoplamento Molecular , Receptor Tipo 1 de Angiotensina/metabolismo , Relação Estrutura-Atividade , Ácido Urocânico/química , Ácido Urocânico/metabolismo
6.
Eur J Med Chem ; 62: 352-70, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23376252

RESUMO

A series of symmetrically bis-substituted imidazole analogs bearing at the N-1 and N-3 two biphenyl moieties ortho substituted either with tetrazole or carboxylate functional groups was designed based on docking studies and utilizing for the first time an extra hydrophobic binding cleft of AT1 receptor. The synthesized analogs were evaluated for their in vitro antagonistic activities (pA2 values) and binding affinities (-logIC50 values) to the Angiotensin II AT1 receptor. Among them, the potassium (-logIC50 = 9.04) and the sodium (-logIC50 = 8.54) salts of 4-butyl-N,N'-bis{[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (12a and 12b, respectively) as well as its free acid 11 (-logIC50 = 9.46) and the 4-butyl-2-hydroxymethyl-N,N'-bis{[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (14) (-logIC50 = 8.37, pA2 = 8.58) showed high binding affinity to the AT1 receptor and high antagonistic activity (potency). The potency was similar or even superior to that of Losartan (-logIC50 = 8.25, pA2 = 8.25). On the contrary, 2-butyl-N,N'-bis{[2'-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (27) (-logIC50 = 5.77) and 2-butyl-4-chloro-5-hydroxymethyl-N,N'-bis{[2'-[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (30) (-logIC50 = 6.38) displayed very low binding affinity indicating that the orientation of the n-butyl group is of primary importance. Docking studies of the representative highly active 12b clearly showed that this molecule has an extra hydrophobic binding feature compared to prototype drug Losartan and it fits to the extra hydrophobic cavity. These results may contribute to the discovery and development of a new class of biologically active molecules through bis-alkylation of the imidazole ring by a convenient and cost effective synthetic strategy.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Desenho de Fármacos , Imidazóis/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Modelos Moleculares , Estrutura Molecular , Teoria Quântica , Relação Estrutura-Atividade
7.
Eur J Med Chem ; 55: 358-74, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22889560

RESUMO

A convenient and facile synthesis, in silico docking studies and in vitro biological evaluation of N-substituted 5-butylimidazole derivatives as potent Angiotensin II (ANG II) receptor type 1 (AT1) blockers (ARBs) has been reported in the current study. Our efforts have been directed towards the development of an efficient synthetic route allowing the facile introduction of substituents on the imidazole ring. In particular, a series of imidazole based compounds bearing the biphenyl moiety at the N - 1 position, a halogen atom at the C-4 and polar substituents such as hydroxymethyl, aldo or carboxy group at the C-2 position were designed and synthesized. These compounds were evaluated for binding to human AT1 receptor and for ANG II antagonism in vitro on isolated rat uterus. Among them, 5-butyl-1-[[2'-(2H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-2-carboxylic acid (30) exhibited higher binding affinity compared to the other analogues tested (-log IC(50) = 8.46). The latter analogue was also found to be the most active in the rat uterotonic test (pA(2) = 7.83). Importantly, the binding affinity was higher to that of losartan (-log IC(50) = 8.25) indicating the importance of carboxy group at the C-2 position. Experimental findings are in good agreement with docking studies, which were undertaken in order to investigate ligand/AT1 receptor interactions.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/síntese química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Descoberta de Drogas , Imidazóis/síntese química , Imidazóis/farmacologia , Simulação de Acoplamento Molecular , Receptor Tipo 1 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo , Animais , Técnicas de Química Sintética , Feminino , Células HEK293 , Humanos , Imidazóis/química , Imidazóis/metabolismo , Técnicas In Vitro , Concentração Inibidora 50 , Conformação Proteica , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/química , Contração Uterina/efeitos dos fármacos , Útero/efeitos dos fármacos , Útero/fisiologia
8.
Amino Acids ; 40(2): 411-20, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20607324

RESUMO

A series of o-, m- and p-benzyl tetrazole derivatives 11a-c has been designed, synthesized and evaluated as potential Angiotensin II AT1 receptor antagonists, based on urocanic acid. Compound 11b with tetrazole moiety at the m-position showed moderate, however, higher activity compared to the o- and p-counterpart analogues. Molecular modelling techniques were performed in order to extract their putative bioactive conformations and explore their binding modes.


Assuntos
Antagonistas de Receptores de Angiotensina/síntese química , Antagonistas de Receptores de Angiotensina/farmacologia , Desenho de Fármacos , Ácido Urocânico/química , Antagonistas de Receptores de Angiotensina/química , Animais , Linhagem Celular , Humanos , Cinética , Masculino , Modelos Moleculares , Ligação Proteica , Coelhos , Ratos , Receptores de Angiotensina/química , Receptores de Angiotensina/metabolismo , Relação Estrutura-Atividade
9.
J Comput Aided Mol Des ; 24(9): 749-58, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20623162

RESUMO

A new 1,5 disubstituted imidazole AT(1) Angiotensin II (AII) receptor antagonist related to losartan with reversion of butyl and hydroxymethyl groups at the 2-, 5-positions of the imidazole ring was synthesized and evaluated for its antagonist activity (V8). In vitro results indicated that the reorientation of butyl and hydroxymethyl groups on the imidazole template of losartan retained high binding affinity to the AT(1) receptor concluding that the spacing of the substituents at the 2,5- positions is of primary importance. The docking studies are confirmed by binding assay results which clearly show a comparable binding score of the designed compound V8 with that of the prototype losartan. An efficient, regioselective and cost effective synthesis renders the new compound as an attractive candidate for advanced toxicological evaluation and a drug against hypertension.


Assuntos
Angiotensina II/antagonistas & inibidores , Antagonistas de Receptores de Angiotensina , Desenho de Fármacos , Losartan/análogos & derivados , Antagonistas de Receptores de Angiotensina/síntese química , Antagonistas de Receptores de Angiotensina/química , Antagonistas de Receptores de Angiotensina/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Humanos , Hipertensão/tratamento farmacológico , Imidazóis/síntese química , Receptores de Angiotensina/química , Receptores de Angiotensina/metabolismo , Receptores de Droga/química , Receptores de Droga/metabolismo , Relação Estrutura-Atividade
10.
Amino Acids ; 38(4): 985-90, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19484400

RESUMO

In the present study, we report the synthesis and biological evaluation of a series of new non-peptide PAR(1) mimetic receptor antagonists, based on conformational analysis of the S(42)FLLR(46) tethered ligand (TL) sequence of PAR(1). These compounds incorporate the key pharmacophore groups in the TL sequence, guanidyl, amino and phenyl, which are essential for triggering receptor activity. Compounds 5 and 15 (50-100 microM) inhibited both TFLLR-amide (10 microM) and thrombin-mediated (0.5 and 1 U/ml; 5 and 10 microM) calcium signaling in a cultured human HEK cell assay.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Mimetismo Molecular , Receptor PAR-1/química , Receptores de Trombina/antagonistas & inibidores , Trombina/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Arginina/análogos & derivados , Arginina/química , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Cicloexanos/síntese química , Cicloexanos/química , Cicloexanos/farmacologia , Dipeptídeos/síntese química , Dipeptídeos/química , Dipeptídeos/farmacologia , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/química , Guanidinas/síntese química , Guanidinas/química , Guanidinas/farmacologia , Humanos , Indóis/síntese química , Indóis/química , Indóis/farmacologia , Ligantes , Oligopeptídeos/antagonistas & inibidores , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Fragmentos de Peptídeos/química , Fenilalanina/análogos & derivados , Fenilalanina/química , Receptor PAR-1/agonistas , Relação Estrutura-Atividade , Trombina/metabolismo
11.
Arch Pharm (Weinheim) ; 342(6): 353-60, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19479749

RESUMO

This report describes the synthesis of unsaturated exomethylene lyxopyranonucleoside analogues as potential biologically active agents. Commercially available 1,2,3,4-tetra-O-acetyl-alpha-D-lyxopyranose 1 was condensed with silylated thymine and uracil, respectively, deacetylated and acetalated to afford 1-(2,3-O-isopropylidene-alpha-D-lyxopyranosyl)thymine 4a and 1-(2,3-O-isopropylidene-alpha-D-lyxopyranosyl)uracil 4b. The new derivatives 1-(2,3,4-trideoxy-4-methylene-alpha-pent-2-enopyranosyl)thymine 8a and 1-(2,3,4-trideoxy-4-methylene-alpha-pent-2-enopyranosyl)uracil 8b were prepared via two different key intermediates, 7a, b and 13a, b in order to elucidate the influence of 2',3'-unsaturation and to clarify the difference between the keto and exomethylene group on the biological activity of the target molecules. Compounds 7a, b, 8a, b, and 13a, b were evaluated for their antiviral and cytostatic activity using several virus strains and cell lines. Whereas no marked antiviral activity was noticed, 13a and 13b showed a cytostatic activity that ranged between 7 and 23 muM for 13a and 26 and 38 muM for 13b against murine leukemia L1210, human lymphocyte Molt4/C8 and CEM cells, and human breast carcinoma MCF7 cells.


Assuntos
Antineoplásicos/farmacologia , Nucleosídeos/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Antivirais/síntese química , Antivirais/química , Antivirais/farmacologia , Células CACO-2 , Linhagem Celular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Camundongos , Nucleosídeos/síntese química , Nucleosídeos/química
12.
Carbohydr Res ; 343(6): 1099-103, 2008 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-18313037

RESUMO

The chemical synthesis of 1,2,4-tri-O-acetyl-3-deoxy-3-fluoro-5-thio-D-xylopyranose, 1,2,4,6-tetra-O-acetyl-3-deoxy-3-fluoro-5-thio-alpha-D-glucopyranose and their corresponding nucleosides of thymine is described. Treatment of 3-fluoro-5-S-acetyl-5-thio-D-xylofuranose, obtained by hydrolysis of the isopropylidene group of 3-fluoro-1,2-O-isopropylidene-5-S-acetyl-5-thio-D-xylofuranose, with methanolic ammonia and direct acetylation, led to triacetylated 3-deoxy-3-fluoro-5-thio-D-xylopyranose. Condensation of acetylated 3-fluoro-5-thio-D-xylopyranose with silylated thymine afforded the corresponding nucleoside. Selective benzoylation and direct methanesulfonylation of 3-fluoro-1,2-O-isopropylidene-alpha-D-glucofuranose gave the 6-O-benzoyl-5-O-methylsulfonyl derivative, which on treatment with sodium methoxide afforded the 5,6-anhydro derivative. Treatment of the latter with thiourea, followed by acetolysis, gave the 3-fluoro-5-S-acetyl-6-O-acetyl-1,2-O-isopropylidene-5-thio-alpha-D-glucofuranose. 3-fluoro-5-S-acetyl-6-O-acetyl-5-thio-D-glucofuranose, obtained after hydrolysis of 5-thiofuranose isopropylidene, was treated with ammonia in methanol and directly acetylated, giving tetraacetylated 3-deoxy-3-fluoro-5-thio-alpha-D-glucopyranose. Condensation of the latter with silylated thymine afforded the desired 3-deoxy-3-fluoro-5-thio-beta-D-glucopyranonucleoside analogue.


Assuntos
Piranos/química , Tioaçúcares/síntese química , Timidina/análogos & derivados , Estrutura Molecular , Timidina/síntese química , Timidina/química
13.
Eur J Med Chem ; 43(2): 420-8, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17548129

RESUMO

The protected beta-nucleosides 1-(2,4,6-tri-O-acetyl-3-deoxy-3-fluoro-beta-d-glucopyranosyl)-N(4)-benzoyl cytosine (2a) and 9-(2,4,6-tri-O-acetyl-3-deoxy-3-fluoro-beta-d-glucopyranosyl)-N(6)-benzoyl adenine (2b), were synthesized by the coupling of peracetylated 3-deoxy-3-fluoro-d-glucopyranose (1) with silylated N(4)-benzoyl cytosine and N(6)-benzoyl adenine, respectively. The nucleosides were deacetylated and several subsequent protection and deprotection steps afforded the partially acetylated nucleosides of cytosine 7a and adenine 7b, respectively. Finally, direct oxidation of the free hydroxyl group at 4'-position of 7a and 7b, and simultaneous elimination reaction of the beta-acetoxyl group, afforded the desired unsaturated 3-fluoro-4-keto-beta-d-glucopyranosyl derivatives. These newly synthesized compounds were evaluated for their potential antitumor and antiviral activities. Compared to 5FU, the newly synthesized derivatives showed to be more efficient as antitumor growth inhibitors and they exhibited direct antiviral effect toward rotavirus.


Assuntos
Adenina/análogos & derivados , Antivirais/síntese química , Antivirais/farmacologia , Citosina/análogos & derivados , Adenina/síntese química , Adenina/farmacologia , Linhagem Celular Tumoral , Citosina/síntese química , Citosina/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Rotavirus/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray
14.
Eur J Med Chem ; 43(7): 1366-75, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18037195

RESUMO

This report describes the total and facile synthesis of the unsaturated keto and exomethylene pyranonucleoside analogues, 1-(2,3,4-trideoxy-4-methylene-6-O-trityl-alpha-D-glycero-hex-2-enopyranosyl)uracil (10), 1-(2,3-dideoxy-alpha-D-glycero-hex-2-enopyranosyl-4-ulose)uracil (17) and 1-(2,3,4-trideoxy-4-methylene-alpha-D-glycero-hex-2-enopyranosyl)uracil (18). Commercially available 1,2,3,4,6-penta-O-acetyl-alpha-D-mannopyranose (1) was condensed with silylated uracil, deacetylated and acetalated to afford 1-(2,3-O-isopropylidene-alpha-D-mannopyranosyl)uracil (4). Two different synthetic routes were investigated for the conversion of 4 into the olefinic derivative 1-(2,3,4-trideoxy-4-methylene-6-O-trityl-alpha-D-glycero-hex-2-enopyranosyl)uracil (10). Although the two procedures are quite similar with respect to yields and final products, the second also leads to the keto-2',3'-unsaturated analogue (17). The new analogues were evaluated for their anticancer and antiviral activities using several tumor cell lines and gastrointestinal rotavirus. All of the compounds showed direct antiviral effect against rotavirus infectivity in Caco-2 cell line. Moreover, 1-(2,3,4-trideoxy-4-methylene-6-O-trityl-alpha-D-glycero-hex-2-enopyranosyl)uracil (10) was found to be potent in MCF-7 breast carcinoma cell line.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Modelos Moleculares , Nucleosídeos/química , Nucleosídeos/farmacologia , Antineoplásicos/síntese química , Antivirais/síntese química , Células CACO-2 , Humanos , Espectroscopia de Ressonância Magnética , Nucleosídeos/síntese química , Rotavirus/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta
15.
Bioorg Med Chem ; 15(16): 5448-56, 2007 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-17555969

RESUMO

A new series of unsaturated pyranonucleosides with an exocyclic methylene group and thymine as heterocyclic base have been designed and synthesized. d-Galactose (1) was readily transformed in three steps into the corresponding 1-(beta-d-galactopyranosyl)thymine (2). Selective protection of the primary hydroxyl group of 2 with a t-butyldimethylsilyl (TBDMS) group, followed by specific acetalation, and oxidation gave 1-(6-O-t-butyldimethylsilyl-3,4-O-isopropylidene-beta-d-lyxo-hexopyranosyl-2-ulose)thymine (5). Wittig reaction of the ketonucleoside 5, deprotection and tritylation of the 6'-hydroxyl group gave 1-(2-deoxy-2-methylene-6-O-trityl-beta-d-lyxo-hexopyranosyl)thymine (9). Exomethylene pyranonucleoside 9 was converted to the olefinic derivative 10, which after detritylation afforded the title compound 1-(2,3,4-trideoxy-2-methylene-beta-d-glycero-hex-3-enopyranosyl)thymine (11). These novel synthesized compounds were evaluated for antiviral activity against rotaviral infection and cytotoxicity in colon cancer. As compared to AZT, compounds 1-(2-deoxy-2-methylene-beta-d-lyxo-hexopyranosyl)thymine (7) and 1-(beta-d-lyxo-hexopyranosyl-2-ulose)thymine (8) showed to be more efficient, in rotavirus infections and in treatment of colon cancer.


Assuntos
Nucleosídeos/química , Nucleosídeos/toxicidade , Timina/análogos & derivados , Timina/síntese química , Timina/toxicidade , Antivirais/síntese química , Antivirais/química , Antivirais/toxicidade , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Concentração Inibidora 50 , Metilação , Estrutura Molecular , Nucleosídeos/síntese química , Relação Estrutura-Atividade , Timina/química
16.
Bioorg Med Chem ; 15(9): 3241-7, 2007 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-17337193

RESUMO

1,2:5,6-Di-O-isopropylidene-alpha-D-glucofuranose by the sequence of mild oxidation, reduction, fluorination, periodate oxidation, borohydride reduction, and sulfonylation gave 3-deoxy-3-fluoro-1,2-O-isopropylidene-5-O-p-toluenesulfonyl-alpha-D-xylofuranose (5). Tosylate 5 was converted to thioacetate derivative 6, which after acetolysis gave 1,2-di-O-acetyl-5-S-acetyl-3-deoxy-3-fluoro-5-thio-D-xylofuranose (7). Condensation of 7 with silylated thymine, uracil, and 5-fluorouracil afforded nucleosides 1-(5-S-acetyl-3-deoxy-3-fluoro-5-thio-beta-D-xylofuranosyl) thymine (8), 1-(5-S-acetyl-3-deoxy-3-fluoro-5-thio-beta-D-xylofuranosyl) uracil (9), and 1-(5-S-acetyl-3-deoxy-3-fluoro-5-thio-beta-D-xylofuranosyl) 5-fluorouracil (10). Compounds 8, 9, and 10 are biologically active against rotavirus infection and the growth of tumor cells.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Xilose/análogos & derivados , Antineoplásicos/química , Antivirais/química , Células CACO-2 , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Fluoruracila/química , Humanos , Intestinos/citologia , Intestinos/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Nucleosídeos/química , Rotavirus/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Timina/química , Uracila/química , Xilose/química , Zidovudina/farmacologia
17.
Bioorg Med Chem ; 15(2): 980-7, 2007 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-17079149

RESUMO

1,2:5,6-Di-O-isopropylidene-alpha-d-glucofuranose on mild oxidation, reduction, fluorination, and deisopropylidenation followed by acetylation gave peracetylated 3-deoxy-3-fluoro-d-glucopyranose. This was coupled with silylated N(4)-benzoyl cytosine. The nucleoside was deacetylated and after several subsequent protection and deprotection steps afforded the desired 3-fluoro-2-keto-beta-d-glucopyranosyl derivatives. These novel synthesized compounds were evaluated for antiviral and cytotoxic activities against rotavirus, vesicular stomatitis virus, and the human colon adenocarcinoma cell line Caco-2, and have a promising potential in combating the rotaviral infections and in the treatment of colon cancer. As compared to AZT, a nucleoside analogue of reverse transcriptase inhibitor, the novel synthesized 1-(3,4-dideoxy-3-fluoro-beta-d-glycero-hex-3-enopyranosyl-2-ulose)-N(4)-benzoyl cytosine showed to be more effective at lower concentrations in inhibition of rotavirus infection as well as in the same range of antitumor activity.


Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Citosina/análogos & derivados , Citosina/síntese química , Citosina/farmacologia , Monossacarídeos/síntese química , Monossacarídeos/farmacologia , Animais , Células CACO-2 , Bovinos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Haplorrinos , Humanos , Indicadores e Reagentes , Oxirredução , Suínos , Vírus da Estomatite Vesicular Indiana/efeitos dos fármacos , Zidovudina/farmacologia
18.
J Med Chem ; 49(1): 105-10, 2006 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-16392796

RESUMO

This report describes the rational design, synthesis, and pharmacological properties of an amide-linked cyclic analogue of gonadotropin-releasing hormone (GnRH) namely Cyclo(4-9)[Lys(4),d-Trp(6),Glu(9)]GnRH. The conformationally restricted analogue is characterized by reduced flexibility of the peptide strand due to the introduction of a beta-turn mimetic through 4,9 residue amide cyclization. The cyclic analogue was found to stimulate gonadotropin gene expression in the goldfish pituitary with similar potency compared to two native forms of GnRH. Simulation studies based on ROE connectivities in linear GnRH and potency of cyclic analogue supports the His(2), Trp(3), Tyr(5) clustering considered important for triggering receptor activation.


Assuntos
Amidas/química , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/análogos & derivados , Gonadotropinas/genética , Modelos Moleculares , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Ciclização , Relação Dose-Resposta a Droga , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Carpa Dourada , Hormônio Liberador de Gonadotropina/síntese química , Hormônio Liberador de Gonadotropina/química , Hormônio Liberador de Gonadotropina/farmacologia , Gonadotropinas/biossíntese , Técnicas In Vitro , Estrutura Molecular , Peptídeos Cíclicos/síntese química , Hipófise/química , Hipófise/citologia , Hipófise/efeitos dos fármacos , Conformação Proteica , RNA Mensageiro/genética
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