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J Med Chem ; 47(27): 6902-13, 2004 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-15615539


In search of active nucleoside 5'-triphosphate mimics, we have synthesized a series of AZT triphosphate mimics (AZT P3Ms) and evaluated their inhibitory effects on HIV-1 reverse transcriptase as well as their stability in fetal calf serum and in CEM cell extracts. Reaction of AZT with 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one, followed by treatment of the phosphite intermediate 2 with pyrophosphate analogues, yielded the cyclic triphosphate intermediates 4b-4f, which were subjected to boronation and subsequent hydrolysis to give AZT 5'-alpha-borano-beta,gamma-bridge-modified triphosphates 6b-6f in moderate to good yields. Reaction of the cyclic intermediate 4d with iodine, followed by treatment with a series of nucleophiles, afforded the AZT 5'-beta,gamma-difluoromethylene-gamma-substituted triphosphates (7b-7i). Several different types of AZT P3Ms containing alpha-P-thio (or dithio) and beta,gamma-difluoromethylene (13,14), alpha,beta-difluoromethylene and gamma-P-methyl(or phenyl) (15,16), and alpha-borano-beta,gamma-difluoromethylene and gamma-O-methyl/phenyl (11,12) were also synthesized. The effectiveness of the compounds as inhibitors of HIV-1 reverse transcriptase was determined using a fluorometric assay and a poly(A) homopolymer as a template. A number of AZT P3Ms exhibited very potent inhibition of HIV-1 reverse transcriptase. Modifications at the beta,gamma-bridge of triphosphate rendered the AZT P3Ms 6b-6f with varied activities (K(i) from 9.5 to >>500 nM) while modification at the alpha,beta-bridge of triphosphate led to weak AZT P3M inhibitors. The results imply that the AZT P3Ms were substrate inhibitors, as is AZT triphosphate. The most active compound, AZT 5'-alpha-R(p)()-borano-beta,gamma-(difluoromethylene)triphosphate (AZT 5'-alphaB-betagammaCF(2)TP) (6d-I), is as potent as AZT triphosphate with a K(i)() value of 9.5 nM and at least 20-fold more stable than AZT triphosphate in the serum and cell extracts. Therefore, for the first time, a highly active and stable nucleoside triphosphate mimic has been identified, which is potentially useful as a new type of antiviral drug. The promising triphosphate mimic, 5'-alpha-borano-beta,gamma-(difluoromethylene)triphosphate, is expected to be valuable to the discovery of nucleotide mimic antiviral drugs.

Transcriptase Reversa do HIV/antagonistas & inibidores , Inibidores da Transcriptase Reversa/síntese química , Zidovudina/análogos & derivados , Estabilidade de Medicamentos , Humanos , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Relação Estrutura-Atividade
Artigo em Inglês | MEDLINE | ID: mdl-15043157


IMPDH inhibitors have potential antimicrobial, anticancer and immunomodulatory effects. Nucleoside inhibitors of IMPDH exert their inhibitory effects via nucleoside 5'-MPs. Conversion of nucleoside analogs to NMPs by cellular nucleoside kinases is not assured, and usually is inefficient. In order to bypass cellular phosphorylation, a series of azole nucleoside 5'-MP mimics (P1Ms) based on ribavirin, EICAR and bredinin were synthesized and screened against human and C. albicans IMP dehydrogenises. P1Ms 8, 16, 25, 28 and 29 demonstrated substantial IMPDH inhibition with Ki values in low micromolar range.

Inibidores Enzimáticos/síntese química , IMP Desidrogenase/antagonistas & inibidores , Nucleotídeos/síntese química , Inibidores Enzimáticos/química , Nucleotídeos/química
Bioorg Med Chem ; 11(23): 5199-201, 2003 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-14604683


An efficient, three-step synthesis of 5'-amino-5'-deoxyaristeromycin (5), from a protected form of aristeromycin (6), is described. Compound 5 was evaluated against a large number of viruses. It showed weak activity towards vaccinia, herpes simplex virus 2, and cytomegalovirus. No other activity was observed. Compound 5 displayed some cytotoxicity towards the host cell lines human foreskin fibroblast, Daudi, and human T-lymphocyte (CEM).

Antivirais/farmacologia , Desoxiadenosinas/farmacologia , Antivirais/química , Linhagem Celular , Citomegalovirus/efeitos dos fármacos , Desoxiadenosinas/química , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Testes de Sensibilidade Microbiana , Vírus Vaccinia/efeitos dos fármacos
Bioorg Med Chem ; 10(4): 883-6, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11836094


(-)-5'-noraristeromycin (1) has shown antiviral activity towards, particularly cytomegalovirus, vaccinia virus and measles while its (+)-enantiomer (2) is effective towards hepatitis B virus. To determine if the antiviral characteristics of 1 and 2 extended to the guanine analogues (3 and 4), these enantiomers were prepared and evaluated against herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), cytomegalovirus (CMV), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6), human herpes virus type 8 (HHV-8), vaccinia virus (VV), cowpox virus (CV), vesicular stomatitis virus (VSV), respiratory syncytial virus (RSV), hepatitis B virus (HBV), and human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The only activity found for 3 was for Epstein-Barr virus in VCA Elisa (EC50 0.78 microg/mL), immunofluorescence assay for VCA or gp 350/250 (1.8-4.0 microg/mL) and DNA hybridization (EC50 0.82 microg/mL) assays with no accompanying toxicity seen in the host Daudi cells. No activity was noted for 4.

Antivirais/síntese química , Guanosina/farmacologia , Herpesvirus Humano 4/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/toxicidade , Guanosina/análogos & derivados , Guanosina/síntese química , Guanosina/toxicidade , Humanos , Testes de Sensibilidade Microbiana , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Vírus/efeitos dos fármacos