RESUMO
On-site sanitation has emerged as a preferred mode of sanitation in cities experiencing rapid urbanization due to the high cost involved in off-site sanitation which requires conventional sewerages. However, this practice has put severe stress on groundwater especially its quality. Under the above backdrop, a study has been undertaken to investigate the impact of on-site sanitation on quality of groundwater sources in two mega cities namely Indore and Kolkata which are situated in two different geological settings. The parameters for the studies are distance of groundwater source from place of sanitation, effect of summer and monsoon seasons, local hydro-geological conditions, and physico-chemical parameters. NO(3) and fecal coliform concentrations are considered as main indexes of pollution in water. Out of many conclusions which can be made from this studies, one major conclusion is about the influence of on-site sanitation on groundwater quality is minimal in Kolkata, whereas it is significant in Indore. This difference is due to the difference in hydrogeological parameters of these two cities, Kolkata being on alluvium quaternary and Indore being on Deccan trap of Cretaceous to Paleogene age.
Assuntos
Monitoramento Ambiental/métodos , Fenômenos Geológicos , Água Subterrânea/análise , Poluentes da Água/química , Poluição Química da Água/prevenção & controle , Índia , Nitratos/química , Estações do Ano , Solo/química , Inquéritos e QuestionáriosRESUMO
BACKGROUND & OBJECTIVE: India has a high prevalence of HIV-1, hapatitis C and B virus (HCV and HBV) in the blood donors but has yet to implement nucleic acid testing (NAT) in blood screening. We undertook a multicentre evaluation of blood donor testing by NAT for simultaneous detection of HIV-1, HBV and HCV in a single tube and also to determine the feasibility of NAT implementation in India's low volume setting. METHODS: A total of 12,224 unlinked samples along with their serological results were obtained from representative eight blood banks in India and were individually manually tested by the Procleix Ultrio Assay (Chiron Corp. Emeryville, CA) for simultaneous detection of HIV-1, HCV, and HBV. RESULTS: Of the 12,224 samples tested, 209 (1.71%) were seroreactive. One hundred thirty three samples (1.09%) were reactive by Ultrio assay, 84 samples were seroreactive but NAT non reactive. There were eight NAT yield cases: 1 HIV, 1 HIV-HCV co-infection, and 6 HBV. INTERPRETATION & CONCLUSION: Our observed NAT yield for all three viruses was 1 in 1528 (0.065%). We estimate NAT could interdict 3272 infectious donations a year among our approximate 5 million annual donations.
Assuntos
Doadores de Sangue , Infecções por HIV/diagnóstico , HIV-1/metabolismo , Hepacivirus/metabolismo , Vírus da Hepatite B/metabolismo , Hepatite B/diagnóstico , Hepatite C/diagnóstico , Programas de Rastreamento/métodos , Técnicas de Amplificação de Ácido Nucleico/normas , RNA Viral/análise , Bancos de Sangue , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/transmissão , Hepatite B/epidemiologia , Hepatite B/transmissão , Hepatite C/epidemiologia , Hepatite C/transmissão , Humanos , Índia , Masculino , Testes Sorológicos/normasRESUMO
Farnesyl protein transferase (FPT) inhibition is an interesting and promising approach to non-cytotoxic anticancer therapy. Research in this area has resulted in several orally active compounds that are currently in clinical evaluation. This review focuses on FPT inhibitors in clinical trials and concentrates on the benzocycloheptapyridine class, with details on the discovery and development of SCH 66336, currently in Phase II clinical trials.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neoplasias/terapia , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Animais , Sítios de Ligação , Ensaios Clínicos como Assunto , Farnesiltranstransferase , Humanos , Estrutura Molecular , Neoplasias/enzimologia , Conformação ProteicaRESUMO
Employing classical conformational analysis on a known H3 agonist, (R)-alpha-methylhistamine (1), a series of conformationally constrained H3 agonists were proposed and synthesized. Pyrrolidine (+/-)-4a, a compound proposed to mimic the anti-conformation of (R)-alpha-methylhistamine (1), was found to be a potent and selective H3 agonist. The pyrrolidine (+/-)-4a was resolved, and its (+) enantiomer, immepyr [(+)-4a], showed a greater separation of H3 and H1 activities in vivo (H3/H1 ratio >> 550) than (R)-alpha-methylhistamine (1) (H3/H1 ratio = 17), the standard H3 agonist. In fact, no evidence of H1 activity was detected at doses of immepyr [(+)-4a] as high as 100 mg/kg i.v. This pyrrolidine, immepyr [(2R,3S)-(+)-4a], represents, to our knowledge, the first reported cyclic, conformationally restricted analog of histamine to possess selective in vivo H3 agonist activity.
Assuntos
Agonistas dos Receptores Histamínicos , Histamina/análogos & derivados , Pirrolidinas/química , Histamina/química , Histamina/farmacologia , Conformação MolecularRESUMO
We previously reported compound 1 as a potent farnesyl protein transferase (FPT) inhibitor that exhibited reasonable pharmacokinetic stability and showed moderate in vivo activity against a variety of tumor cell lines. The analogous C-11 single compound, pyridylacetamide 2, was found to be more potent than 1 in FPT inhibition. Further studies showed that modification of the ethano bridge of the tricyclic ring system by conversion into a double bond with concomitant introduction of a single bond at C-11 piperidine resulted in compound 3 that had superior FPT activity and pharmacokinetic stability. Compound 4, a 5-bromo-substituted analogue of 3, showed improved FPT activity, had good cellular activity, and demonstrated a remarkably improved pharmacokinetic profile with AUC of 84.9 and t1/2 of 82 min. Compound4 inhibited the growth of solid tumor in DLD-1 model by 70% at 50 mpk and 52% at 10 mpk.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos , Óxidos N-Cíclicos , Inibidores Enzimáticos , Piridinas , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/síntese química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Óxidos N-Cíclicos/administração & dosagem , Óxidos N-Cíclicos/síntese química , Óxidos N-Cíclicos/farmacocinética , Óxidos N-Cíclicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Transplante de Neoplasias , Proteína Oncogênica p21(ras)/antagonistas & inibidores , Piridinas/administração & dosagem , Piridinas/síntese química , Piridinas/farmacocinética , Piridinas/farmacologia , Células Tumorais CultivadasRESUMO
The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl) piperazine to explore the SAR of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b (+/-) and 85b [11S(-)] and the 4-carboxamidopiperidinylacetamido derivative 160b (+/-), all of which exhibited potent FPT inhibition in vitro. All three showed excellent oral bioavailability in vivo in nude mice and cynomolgus monkeys and exhibited excellent antitumor efficacy against a series of tumor cell lines when dosed orally in nude mice.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/síntese química , Óxidos N-Cíclicos/síntese química , Inibidores Enzimáticos/síntese química , Piperazinas/síntese química , Piperidinas/síntese química , Células 3T3 , Administração Oral , Animais , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Disponibilidade Biológica , Células COS , Linhagem Celular Transformada , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/metabolismo , Óxidos N-Cíclicos/farmacocinética , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Genes ras , Macaca fascicularis , Camundongos , Camundongos Nus , Transplante de Neoplasias , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacocinética , Piperidinas/química , Piperidinas/metabolismo , Piperidinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Novel tricyclic Ras farnesyl-protein transferase (FPT) inhibitors are described. A comprehensive structure-activity relationship (SAR) study of compounds arising from substitution at the 3-position of the tricyclic pyridine ring system has been explored. In the case of halogens, the chloro, bromo, and iodo analogues 19, 22, and 28 were found to be equipotent. However, the fluoro analogue 17 was an order of magnitude less active. Whereas a small alkyl substituent such as a methyl group resulted in a very potent FPT inhibitor (SCH 56580), introduction of bulky substituents such as tert-butyl, compound 33, or a phenyl group, compound 29, resulted in inactive FPT inhibitors. Polar groups at the 3-position such as amino 5, alkylamino 6, and hydroxyl 12 were less active. Whereas compound SCH 44342 did not show appreciable in vivo antitumor activity, the 3-bromo-substituted pyridyl N-oxide amide analogue 38 was a potent FPT inhibitor that reduced tumor growth by 81% when administered q.i.d. at 50 mpk and 52% at 10 mpk. These compounds are nonpeptidic and do not contain sulfhydryl groups. They selectively inhibit FPT and not geranylgeranyl-protein transferase-1 (GGPT-1). They also inhibit H-Ras processing in COS monkey kidney cells and soft agar growth of Ras-transformed cells.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , Piperidinas/síntese química , Piridinas/síntese química , Células 3T3 , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Células COS , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Piperidinas/química , Piperidinas/farmacologia , Prenilação de Proteína , Piridinas/farmacologia , Relação Estrutura-Atividade , Transfecção/genética , Proteínas ras/metabolismoRESUMO
Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with novel tricyclic inhibitors provide insights into the observed SAR for this unique class of nonpeptidic FPT inhibitors. The crystallographic structures reveal a binding pattern conserved across the mono-, di-, and trihalogen series. In the complexes, the tricycle spans the FPT active site cavity and interacts with both protein atoms and the isoprenoid portion of bound farnesyl diphosphate. An amide carbonyl, common to the tricyclic compounds described here, participates in a water-mediated hydrogen bond to the protein backbone. Ten high-resolution crystal structures of inhibitors complexed with FPT are reported. Included are crystallographic data for FPT complexed with SCH 66336, a compound currently undergoing clinical trials as an anticancer agent (SCH 66336, 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarbo xamide ). Thermodynamic binding parameters show favorable enthalpies of complex formation and small net entropic contributions as observed for 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-11H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]pyridine N-oxide where DeltaH degrees bind = -12.5 kcal/mol and TDeltaS degrees bind = -1.5 kcal/mol.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/química , Óxidos N-Cíclicos/química , Inibidores Enzimáticos/química , Compostos Heterocíclicos com 3 Anéis/química , Piperidinas/química , Prenilação de Proteína , Piridinas/química , Sítios de Ligação , Calorimetria , Cristalografia por Raios X , Ligação de Hidrogênio , Modelos Moleculares , TermodinâmicaRESUMO
Farnesyl protein transferase (FPT) is a promising target for the development of cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Piperidinas/síntese química , Piridinas/síntese química , Sulfonamidas/síntese química , Compostos de Sulfonilureia/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Células COS , Divisão Celular/efeitos dos fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Haplorrinos , Camundongos , Camundongos Nus , Piperidinas/química , Piperidinas/farmacocinética , Prenilação de Proteína , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Piridinas/química , Piridinas/farmacocinética , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacocinética , Compostos de Sulfonilureia/química , Compostos de Sulfonilureia/farmacocinéticaRESUMO
We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antineoplásicos/síntese química , Inibidores Enzimáticos/síntese química , Piperidinas/síntese química , Prenilação de Proteína/efeitos dos fármacos , Piridinas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Células COS , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Macaca fascicularis , Camundongos , Camundongos Nus , Piperidinas/química , Piperidinas/farmacocinética , Piperidinas/farmacologia , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
An intimate relation between polyamines and cellular growth is evident from the existing literature; but the role of polyamines in carcinomatous growth has not been established and it remains a controversy whether polyamine analysis can be of any use as a marker for carcinoma. In an attempt to find out the relation of polyamine to carcinomatous tissues, it has been found that putrescine, cadaverine, spermine and spermidine concentrations in breast, rectal and squamous cell carcinomatous tissues, analysed under the present experiment, increased unequivocally. The result has been discussed and a reasonable explanation has been given to support the finding.
Assuntos
Neoplasias da Mama/análise , Carcinoma de Células Escamosas/análise , Poliaminas/análise , Neoplasias Retais/análise , Adulto , Amina Oxidase (contendo Cobre)/análise , Feminino , Humanos , Pessoa de Meia-Idade , Ornitina Descarboxilase/metabolismoRESUMO
In view of the controversy that exists regarding the histamine content and diamine oxidase activity in relation to human carcinomatous growths, the present investigation was undertaken and carcinomatous tissues of skin, breast and rectum were analysed. The result of the experiment gives a clear evidence that both histamine concentration and diamine-oxidase activity increase significantly in all the three types of growth. The result has been discussed and a reasonable explanation has been offered for the observations made.
Assuntos
Amina Oxidase (contendo Cobre)/análise , Neoplasias da Mama/análise , Carcinoma/análise , Histamina/análise , Neoplasias Retais/análise , Neoplasias Cutâneas/análise , Adulto , Feminino , Histidina Descarboxilase/análise , Humanos , Pessoa de Meia-IdadeRESUMO
In view of the conflicting reports regarding the association of di- and poly-amines along with diamine oxidase (DAO) activity in human carcinomatous growths, the present study was undertaken to establish their interrelation and to justify whether analysis of di- and poly-amine contents along with DAO may have any diagnostic value in the assessment of the carcinomatous state. It was found that diamines like histamine, putrescine and cadaverine, and polyamines like spermine and spermidine, and also DAO, increased unequivocally in human ovarian, cervical and endometrial carcinoma in comparison with their adjoining normal tissues. A reasonable explanation has been put forward to support the observations made.
Assuntos
Amina Oxidase (contendo Cobre)/metabolismo , Poliaminas Biogênicas/metabolismo , Diaminas/metabolismo , Neoplasias do Endométrio/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias do Colo do Útero/metabolismo , Adulto , Cadaverina/metabolismo , Neoplasias do Endométrio/enzimologia , Feminino , Histamina/metabolismo , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/enzimologia , Putrescina/metabolismo , Valores de Referência , Espermidina/metabolismo , Espermina/metabolismo , Neoplasias do Colo do Útero/enzimologiaRESUMO
A novel mass spectrometry-based methodology using electrospray ionization (ESI) is described for the detection of protein-protein [interferon (IFN)-γ dimer] and protein-ligand [ras-guanosine diphosphate (GDP)] noncovalent interactions. The method utilizes ESI from aqueous solution at appropriate pH. The presence of the noncovalent complex of the IFN-γ dimer was confirmed by the observed average molecular weight of 33,819 Da. The key to the detection of the IFN-γ dimer is the use of an alkaline solution (pH ≈ 9) for sample preparation and for mass spectrornetry analysis. The effect of the declustering energy in the region of the ion sampling orifice and focusing quadrupole on the preservation of the gas-phase noncovalent complex (IFN-γ dimer) was also studied. The effect of the declustering energy on complex dissociation was further extended to probe the noncovalent protein-ligand association of ras-GDP. It was found that little energy is required to dissociate the IFN-γ dimer, whereas a substantial amount of energy is required to dissociate the gas-phase ras-GDP complex.
RESUMO
[formula: see text] Synthesis of C-11 methyl-substituted benzocycloheptylpyridine tricyclic compounds has been achieved via two different methods. Methylation of C-11 has been effected by treatment of amine 4 with BuLi followed by Mel quenching. In a similar procedure, introduction of a C-11 substituent with concomitant rearrangement of the exocyclic double bond has been carried out. Potent farnesyl protein transferase inhibitors have been synthesized using the above methodologies.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Piridinas/síntese química , Inibidores Enzimáticos/farmacologia , Piridinas/farmacologiaRESUMO
The detection of non-covalent complexes in the mass range 19,000-34,000 Da, using electrospray ionization mass spectrometry (ESI-MS), is reviewed. The examples discussed include (1) a protein-ligand interaction (ras-GDP), (2) an inhibitor-protein-ligand interaction (SCH 54292/SCH 54341-ras-GDP), (3) a protein-protein interaction (gamma-IFN homodimer) and (4) a protein-metal complex [HCV (1-181)-Zn]. In each case, the ESI-MS method is capable of releasing the intact non-covalent complex from its native solution state into the gas phase in the form of multiply-charge ions. The molecular masses of these complexes were determined with a mass accuracy of better than 0.01%, which is far superior to the traditional methods of sodium dodecyl sulfate polyacrylamide gel electrophoresis and gel permeation chromatography. The method provides the researcher with a quick, reliable and reproducible method for probing difficult biological problems. The key to success in the study of non-covalent complexes depends on careful understanding and manipulation of ESI source parameters and sample solution conditions; special care must be taken with the source orifice potential and the solution pH and organic co-solvents must be avoided. This paper also illustrates the usefulness of ESI-MS for addressing biological problems leading to the discovery of new therapeutics; the approach involves the rapid screening of potential drug candidates, such as weakly bound inhibitors.
Assuntos
Espectrometria de Massas/métodos , Proteínas/química , Quelantes/química , Genes ras , Glucosídeos/análise , Guanosina Difosfato/análise , Hepacivirus/química , Humanos , Interferon gama/química , Ligantes , Espectrometria de Massas/instrumentação , Metais/química , Peso Molecular , Proteínas/análise , Sulfonamidas/análiseRESUMO
High-resolution mass spectrometry has been routinely used for structural confirmation and identification; however, it has mostly been applied to relatively pure samples. Exact mass measurement of minor components such as impurities, degradation products or metabolites in complex mixtures has been difficult without prior separation and isolation. Here we report the utilization of on-line liquid chromatography in combination with high-resolution mass spectrometry for the identification of impurities and base degradation products of Sch 27899, a member of the everninomicin class of antibiotics. Nine Sch 27899-related impurities and degradation products were detected by negative ion electrospray ionization using a magnetic sector mass spectrometer. Exact mass measurements were obtained at a resolution of 5000 using polyethylene glycol (PEG) sulfates as internal standards. Corresponding elemental compositions were determined within a 2 ppm error tolerance and structures were proposed for all components.
Assuntos
Aminoglicosídeos , Antibacterianos/química , Antibacterianos/metabolismo , Cromatografia Líquida/métodos , Oligossacarídeos/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Antibacterianos/análise , Calibragem , Sequência de Carboidratos , Micromonospora/química , Dados de Sequência Molecular , Estrutura Molecular , Oligossacarídeos/química , Oligossacarídeos/metabolismo , Sensibilidade e EspecificidadeRESUMO
Ziracin is produced by Micromonospora carbonacea and is highly active against Gram-positive bacteria. In particular it is highly active against methicillin resistant staphylococci and vancomycin resistant enterococci. Ziracin, C71H97NO38Cl2, contains two orthoester linkages, a nitro sugar, a methylene dioxy group, two aromatic ester residues and thirty five centres of assymmetries. In this paper a brief description of the structural elucidation of ziracin is presented along with the chemical modification of the antibiotic which has led to the identification of several potent antibacterials.
Assuntos
Aminoglicosídeos , Antibacterianos , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Infecções por Bactérias Gram-Positivas/microbiologia , Cocos Gram-Positivos/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Humanos , Estrutura Molecular , Oligossacarídeos/química , Relação Estrutura-AtividadeRESUMO
Novel antibiotic everninomicin D is chemically transformed into new biologically active derivatives. Reactions of a nitro group attached to a tertiary carbon center have been investigated. Synthesis and reactions of hydroxylaminoeverninomicin D, aminoeverninomicin D and their derivatives have been discussed.
Assuntos
Aminoglicosídeos , Antibacterianos/síntese química , Animais , Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Infecções Bacterianas/tratamento farmacológico , Fenômenos Químicos , Química , Estabilidade de Medicamentos , Glicosídeos/síntese química , Glicosídeos/farmacologia , Glicosídeos/uso terapêutico , RatosRESUMO
From a series of amide analogs of the histamine H1 antagonist, azatadine, a potent, orally active, dual platelet-activating factor (PAF) and histamine antagonist, Sch 37370, namely 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo- [5,6]cyclohepta[1,2-b]pyridin-11-ylidine)piperidine, was discovered. Sch 37370 selectively inhibits PAF-induced aggregation of human platelets in vitro (IC50 = 0.6 microM), and in vivo inhibits PAF- and histamine-induced bronchospasm in guinea pigs with ED50 values of 6.0 and 2.4 mg/kg p.o., respectively. Sch 37370 is expected to be more efficacious than single mediator antagonists in allergic diseases, such as asthma.