RESUMO
Structural interpretation of the 31P NMR shifts measured in O,O-diethyl thiophosphate (PT), 5,5-dimethyl-2-mercapto-1,3,2-dioxaphosphorinane 2-oxide (cPT), diethylphosphate (P) and 5,5-dimethyl-2-hydroxy-1,3,2-dioxaphosphinane 2-oxide (cP) was obtained by means of theoretical calculations including the effects of geometry, molecular dynamics, and solvent, relativistic effects and the effect of NMR reference. NMR calculations employed the B3LYP, BP86, BPW91, M06-2X, PBE0, MP2, and HF methods, the Iglo-n (n = II, III), cc-pVnZ (n = D, T, Q, 5), and pcS-n (n = 0, 1, 2, 3, 4) Gaussian-type basis sets and the Slater-type QZ4P atomic basis. Water solvent was described explicitly and/or implicitly. The effects due to molecular dynamics were calculated using molecular dynamics simulations with the GAFF force field and the TIP3P water molecules, and alternatively by means of the zero-point ro-vibrational averaging. Relativistic effects included the spin-orbit calculated within the two-component zero-order relativistic approximation and the effect with the four-component DFT method. Optimal geometries and large-amplitude dynamical motions within the "opened" PT and P molecules contrasted with notably different geometries and confined dynamical motions within the cPT and cP "closed" molecules. These structure-dynamical differences together with the different chemical structures of thiophosphate and phosphate due to a non-esterified sulphur or oxygen atom within the group considerably affected the magnitudes of 31P NMR shifts. The theoretical calculations enabled accurate and reliable structure-dynamical interpretation of the measured 31P NMR shifts. The effects due to explicit solvent and relativity turned out to be indispensable for obtaining accurate 31P NMR shifts particularly in the thiophosphates. Replacement of the non-esterified oxygen atom in the phosphate with sulphur makes NMR shielding of the phosphorus atom qualitatively different as compared to the NMR shielding of the phosphorus atom in phosphate, H3PO4 and PH3.
RESUMO
We have prepared and studied a series of new brassinosteroid derivatives with a p-substituted phenyl group in the side chain. To obtain the best comparison between molecular docking and biological activities both types of brassinosteroids were synthesized; 6-ketones, 10 examples, and B-lactones, 8 examples. The phenyl group was introduced into the steroid skeleton by Horner-Wadsworth-Emmons. The docking studies were carried out using AutoDock Vina 1.05. Plant biological activities were established using different brassinosteroid bioassays in comparison with natural brassinosteroids. Differences in the production of the plant hormone ethylene were also observed in etiolated pea seedlings after treatment with new brassinosteroids. The most active compounds were lactone 8f and 6-oxo derivatives 8c and 9c, their biological activities were comparable or even better than naturally occurring brassinolide. Finally the cytotoxicity of the new derivatives was studied using human normal and cancer cell lines.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Brassinosteroides/química , Brassinosteroides/farmacologia , Antineoplásicos/metabolismo , Arabidopsis/metabolismo , Proteínas de Arabidopsis/metabolismo , Brassinosteroides/metabolismo , Linhagem Celular Tumoral , Humanos , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Reguladores de Crescimento de Plantas/metabolismo , Proteínas Quinases/metabolismoRESUMO
Synthetic study on cystinyl peptides using solution and solid phase methodology was carried out with the central hinge region of immunoglobulin IgG1. In the solid phase synthesis of hexadecapeptide 1c, the time necessary for the formation of disulfide bonds between linear precursors was shortened four times by the action of pure oxygen in buffered solution, in comparison with air oxidation. The product was thus obtained devoid of impurities from side reactions. In the preparation of the shortened bis-cystinyl analogs 2k and 3d of the natural hexadecapeptide 1c, both the classical and polyethylene glycol (PEG6000) solution methods were utilized using a disulfide synthon (Boc-Cys-OPfp)2 to obtain peptide chains in a natural parallel alignment. In the PEG6000 strategy, lysine as a linker on both sides of the polymer was attached to enhance the loading capacity. The leucine residue, instead of proline one, was introduced to the carboxy terminus to facilitate a specific enzymatic cleavage of the peptides from PEG6000 by thermolysine.
Assuntos
Química Orgânica/métodos , Imunoglobulina G/química , Peptídeos/síntese química , Sequência de Aminoácidos , Humanos , Dados de Sequência Molecular , Peptídeos/químicaRESUMO
A series of N (alpha)-acyl (alkyl)- and N (alpha)-alkoxycarbonyl-derivatives of L- and D-ornithine were prepared, characterized, and analyzed for their potency toward the bacterial enzyme N (alpha)-acetyl-L-ornithine deacetylase (ArgE). ArgE catalyzes the conversion of N (alpha)-acetyl-L-ornithine to L-ornithine in the fifth step of the biosynthetic pathway for arginine, a necessary step for bacterial growth. Most of the compounds tested provided IC(50) values in the muM range toward ArgE, indicating that they are moderately strong inhibitors. N (alpha)-chloroacetyl-L-ornithine (1g) was the best inhibitor tested toward ArgE providing an IC(50) value of 85 microM while N (alpha)-trifluoroacetyl-L-ornithine (1f), N (alpha)-ethoxycarbonyl-L-ornithine (2b), and N (alpha)-acetyl-D-ornithine (1a) weakly inhibited ArgE activity providing IC(50) values between 200 and 410 microM. Weak inhibitory potency toward Bacillus subtilis-168 for N (alpha)-acetyl-D-ornithine (1a) and N (alpha)-fluoro- (1f), N (alpha)-chloro- (1g), N (alpha)-dichloro- (1h), and N (alpha)-trichloroacetyl-ornithine (1i) was also observed. These data correlate well with the IC(50) values determined for ArgE, suggesting that these compounds might be capable of getting across the cell membrane and that ArgE is likely the bacterial enzymatic target.
Assuntos
Amidoidrolases/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Proteínas de Escherichia coli/antagonistas & inibidores , Ornitina/análogos & derivados , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Cinética , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peso Molecular , Ornitina/síntese química , Ornitina/química , Ornitina/farmacologia , Fosgênio/análogos & derivados , Fosgênio/química , Poliestirenos/química , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
The disulfide bridge closed cyclic peptide corresponding to the whole Consensus V3 loop of the envelope protein gp120 of HIV-1 was examined by proton 2D-NMR spectroscopy in water and in a 20% trifluoroethanol/water solution. In water, NOE data support a beta-turn conformation for the central conservative GPGR region and point towards partial formation of a helix in the C-terminal part. Upon addition of trifluoroethanol, a C-terminal helix is formed. This is evidenced by NOE data, alpha-proton chemical shift changes and changes in the JN alpha vicinal coupling constants. The C-terminal helix is amphipathic and also occurs in other examined strains. It could therefore be an important feature for the functioning of the V3 loop.
Assuntos
Proteína gp120 do Envelope de HIV/química , Fragmentos de Peptídeos/química , Sequência de Aminoácidos , Sequência Consenso , Espectroscopia de Ressonância Magnética , Dados de Sequência Molecular , Conformação Proteica , Alinhamento de Sequência , Soluções , Trifluoretanol/química , Água/químicaRESUMO
O-Phosphonatomethylcholine, an isopolar phosphocholine analogue with a phosphonomethyl ether group replacing a phosphomonoester residue, was prepared by reaction of diisopropyl 2-chloroethoxymethylphosphonate with dimethylamine followed by quaternization of the thus-obtained diisopropyl 2-dimethylaminoethoxymethylphosphonate with iodomethane; the ester groups in the quaternary intermediate were cleaved with bromotrimethylsilane. Replacement of dimethylamine in the reaction sequence by morpholine and/or pyrrolidine gave the N-methylmorpholinium or N-methylpyrrolidinium analogues of O-phosphonatomethylcholine. Reaction of O-phosphonomethylcholine monotetrabutylammonium salt with 1-bromoalkanes in acetonitrile afforded a series of the corresponding monoalkyl (C10-C16) esters. None of these compounds except for the hexadecyl ester exhibited any appreciable cytostatic activity against DU-145, H460, HT-29, or MES-SA cell lines in vitro (evaluated by 3H-Thd incorporation assay). The hexadecyl ester exhibited modest in vitro cytotoxic activity comparable to that of the anticancer drug miltefosine (hexadecyl O-phosphocholine). In vivo evaluation of hexadecyl O-phosphonomethylcholine [transplanted SD lymphoma in inbred SD/cub rats, 10 mg kg(-1) day(-1) intratumoral injection for 10 days] resulted in a 40% decrease in lymphoma mass.
Assuntos
Antineoplásicos/síntese química , Colina/síntese química , Organofosfonatos/síntese química , Fosforilcolina/análogos & derivados , Fosforilcolina/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Colina/análogos & derivados , Colina/química , Colina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Organofosfonatos/química , Organofosfonatos/farmacologia , Fosforilcolina/química , Fosforilcolina/farmacologia , Ratos , Relação Estrutura-Atividade , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
Reaction of phosphoroorganic synthons with 8-azaadenine, 8-aza-2, 6-diaminopurine, and 8-azaguanine using cesium carbonate yielded regioisomeric 8-azapurine N7-, N8-, and N9-(2-(phosphonomethoxy)alkyl) derivatives. This reaction followed by deprotection afforded isomeric 2-(phosphonomethoxy)ethyl (PME), (S)-(3-hydroxy-2-(phosphonomethoxy)propyl) [(S)-HPMP], (S)-(3-flouro-2-(phosphonomethoxy)propyl) [(S)-FPMP], (S)-(2-(phosphonomethoxy)propyl) [(S)-PMP], and (R)-(2-(phosphonomethoxy)propyl) [(R)-PMP] derivatives. 13C NMR spectra were used for structural assignment of the regioisomers. None of the 8-isomers exhibited any antiviral activity against herpesviruses, Moloney murine sarcoma virus (MSV), and/or HIV. 9-(S)-HPMP-8-azaadenine (23) and PME-8-azaguanine (65) were active against HSV-1, HSV-2, and CMV at 0.2-7 micrograms/mL, VZV at 0.04-0.4 microgram/mL, and MSV (at 0.3-0.6 microgram/mL). PME-8-azaguanine (65) and (R)-PMP-8-azaguanine (71a) protected MT-4 and CEM cells against HIV-1- and HIV-2-induced cytopathicity at a concentration of approximately 2 micrograms/mL.
Assuntos
Adenina/análogos & derivados , Antivirais/síntese química , Guanina/análogos & derivados , Purinas/química , Células 3T3 , Adenina/síntese química , Adenina/farmacologia , Animais , Antivirais/farmacologia , Transformação Celular Viral/efeitos dos fármacos , Citomegalovirus/efeitos dos fármacos , Efeito Citopatogênico Viral/efeitos dos fármacos , Guanina/síntese química , Guanina/farmacologia , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Herpesvirus Humano 3/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos C3H , Estrutura Molecular , Vírus do Sarcoma Murino/efeitos dos fármacosRESUMO
Careful epoxidation of the delta 16-olefins 3 and 4 yielded 16 alpha,17 alpha-epoxides 5 and 6 which were reduced by lithium aluminium hydride, oxidized, and dehydrated to 17 alpha-hydroxycholest-4-en-3-one 20, i.e., an epitestosterone homolog containing a well tolerated alkyl group at position 17. Under catalysis of acids, epoxide 5 was rearranged to delta 13-16 alpha-alcohol 10. Less careful epoxidation of delta 16-olefin 4 with excess of peroxy acid led to products of double epoxidation (i.e., epoxidation, rearrangement, and another oxidation) 7 and 12. Structures of products of rearrangement were studied mainly by NMR spectroscopy.
Assuntos
Colestanóis/síntese química , Epitestosterona/análogos & derivados , Alcenos/química , Compostos de Epóxi , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxirredução , Espectrofotometria InfravermelhoRESUMO
Microbial transformation experiments were conducted with the antitumor lactone withaferin-A. Cunninghamella elegans NRRL 1393 transformed withaferin-A (1a) to 15 beta-hydroxywithaferin-A (2a) and 12 beta-hydroxy-withaferin-A (3a). The hydroxylated metabolites were isolated by solvent extraction and were purified by column and thin-layer chromatography. Structures of the hydroxylated metabolites were determined by proton-and carbon-13 NMR, IR and mass spectral analyses, and by the preparation of acylated derivatives. Compounds 2a and 3a inhibited the growth and biochemical functions of in vitro grown P-388 lymphocytic leukemic cells.
Assuntos
Antineoplásicos Fitogênicos/metabolismo , Ergosterol/análogos & derivados , Mucorales/metabolismo , Animais , Biotransformação , Ergosterol/metabolismo , Fermentação , Leucemia P388/tratamento farmacológico , Espectroscopia de Ressonância Magnética , Camundongos , VitanolídeosRESUMO
Treatment of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-1-thio-beta-D-glucopyranose with 1,6-anhydro-3,4-dideoxy-2-O-p-toluenesulfonyl-beta-D-erythro-hex-3-enopyranose gave 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-beta-D-glucopyranosyl-(1-->4)-1,6-anhydro-2,3-dideoxy-4-thio-beta-D-erythro-hex-2-enopyranose in 86% yield. Its 1,6-anhydride bond was cleaved with methanol to give a mixture of methyl glycosides (alpha/beta approximately 5:1), from which the alpha anomer was separated by crystallization and converted into its 6-acetate, 6-methanesulfonate, or deacetylated to obtain the corresponding free methyl thiodisaccharide. The structure of the new compounds was confirmed by 1H and 13C NMR spectra.
Assuntos
Amino Açúcares/síntese química , Dissacarídeos/síntese química , Tioglucosídeos/síntese química , Espectroscopia de Ressonância MagnéticaRESUMO
The Thormählen positive melanogen previously determined as "A" has been isolated from melanotic urine by means of column chromatography on Amberlite IR 45, DEAE cellulose and Dowex 50. According to its behavior during a study with 1H--NMR spectra it has been found that the isolatd compound is 6-methoxy-5-indolyglucosiduronate, the metabolite of 5,6-dihydroxyindole. The possible formation and biotransformation of this compound is discussed.
Assuntos
Indóis/urina , Melaninas/urina , Melanoma/urina , Cromatografia DEAE-Celulose , Cromatografia em Papel , Humanos , Metástase NeoplásicaRESUMO
In this report we present a novel, simple way for the synthesis of 3'-C-phosphonate derivatives of all four basic 2'-deoxynucleosides in both fully protected and deprotected forms. The reactivity of the geminal hydroxy phosphonate moiety located at the 3'-carbon atom of the nucleoside was studied with respect to the use of this type of nucleoside phosphonic acid for the preparation of short oligonucleotides, namely, dinucleoside monophosphate analogues.
Assuntos
DNA/síntese química , Desoxirribonucleosídeos/química , Desoxirribonucleosídeos/síntese química , Organofosfonatos/química , Organofosfonatos/síntese química , Espectroscopia de Ressonância Magnética , Modelos Químicos , EspectrofotometriaRESUMO
A case is presented of Fabry's disease manifesting in an adult (aged 64) as hypertrophic nonobstructive cardiomyopathy caused by massive ceramidtrihexoside storage confined exclusively to the cardiocytes. There was no storage detectable in capillaries or in any other structure of the organs examined (liver, pancreas, brain, aorta, pulmonary artery, coronary arteries, heart valves). The clinical picture was dominated by heart failure slowly progressing during the last fifteen years of the patient's life terminated by pulmonary thromboembolism. There were no clinical signs of ocular, renal or skin affection. Since no unfixed tissues were available for enzyme analysis diagnosis had to be done using formaldehyde fixed tissues. The isolated stored lipid was characterized by TLC and by proton magnetic resonance analysis as globotriaosyl ceramide (Gal alpha 1-4 Gal beta 1-4 Glc beta 1-1' Cer) and was proved to be cleaved by control cell homogenates but left intact by those prepared from Fabry mutant cells (leukocytes, cultured fibroblasts). alpha galactosidase activity in each of his four daughters was in heterozygous range (peripheral leukocytes were used for analysis). The existing variants of cardiological syndromes in Fabry's disease are reviewed together with problems of diagnosis of atypical cases.
Assuntos
Cardiomiopatia Hipertrófica/etiologia , Doença de Fabry/complicações , Cardiomiopatia Hipertrófica/diagnóstico , Diagnóstico Diferencial , Doença de Fabry/diagnóstico , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
From an ethanolic extract of the flower buds of Cynara cardunculus L. (Asteraceae), two monodesmosidic saponins, cynarasaponin B and a new cynarasaponin K, were isolated. The isolated compounds were identified by spectroscopic means and by comparison with standards and the literature data.
Assuntos
Asteraceae/química , Estruturas Vegetais/química , Saponinas/isolamento & purificação , Saponinas/química , Verduras/químicaRESUMO
The paper deals with the isolation of constituents from light petrol and methanol extracts of the leaves of Holodiscus discolor (PURSH) MAXIM., Rosaceae. beta-sitosterol and taraxasterol were isolated from the light petrol extract, luteolin-7-O-glucoside was isolated from the methanol extract. The isolated compounds were identified by spectroscopic means and by comparison with authentic samples.
Assuntos
Luteolina , Folhas de Planta/química , Plantas Medicinais/química , Rosaceae/química , Flavonoides/isolamento & purificação , Glucosídeos/isolamento & purificação , Sitosteroides/isolamento & purificação , Esteróis/isolamento & purificação , Triterpenos/isolamento & purificaçãoRESUMO
From the butanolic extract of petals of Lilium candidum L., beta-sitosterol and beta-sitosterol glucoside were isolated. The isolated compounds were identified by spectroscopic means and by comparison with literature data; beta-sitosterol glucoside was isolated in genus Lilium L. for the first time.
Assuntos
Extratos Vegetais/isolamento & purificação , Sitosteroides/isolamento & purificação , Extratos Vegetais/química , Sitosteroides/químicaRESUMO
The paper deals with the isolation of constituents from light petrol and chloroform extracts of the leaves of Philadelphus coronarius L., Saxifragaceae. From the light petrol extract uvaol and 3 beta,28-dihydroxyoleanane-11(12),13(18)-diene were isolated, while coumarins (umbelliferone, scopolin), stigmasteryl-3 beta-D-glucoside and the alcane type carbohydrate-C29H60 were isolated from the chloroform extract. The isolated compounds were identified by spectroscopic means and by comparison with standards and the literature data.
Assuntos
Cumarínicos/isolamento & purificação , Folhas de Planta/química , Plantas Medicinais/química , Triterpenos/isolamento & purificação , Extratos Vegetais/químicaRESUMO
The search for potential inhibitors that target so far unexplored bacterial enzyme mono-N-succinyl-L,L-diaminopimelic acid desuccinylase (DapE) has stimulated a development of methodology for quick and efficient preparation of mono-N-acylated 2,6-diaminopimelic acid (DAP) derivatives bearing the different carboxyl groups or lipophilic moieties on their amino group.