RESUMEN
A series of 2',3'-didehydro-2',3'-dideoxynucleosides substituted with an alkynylhydroxy- (6, 7, 12 and 13) and alkynylamino- (20) groups at the C-5 position were synthesized. All these five target modified nucleosides were tested for anti-human immunodeficiency virus type 1 activity in CEM-SS and MT-4 cells and unfortunately displayed no improvement in antiviral activity.
Asunto(s)
Alquinos/química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Estavudina , Fármacos Anti-VIH/química , Línea Celular , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , VIH-1/efectos de los fármacos , VIH-1/fisiología , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Inhibidores de la Transcriptasa Inversa/química , Estavudina/análogos & derivados , Estavudina/síntesis química , Estavudina/farmacología , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Expected for the ability to inhibit HIV replication, we report the synthesis of two heterodimers of the general formula: [2NRTI]-C5-GLY-SUCCINYL-Npiperazinyl-[NNRTI] (18, 19) containing both a Nucleoside Reverse Transcriptase Inhibitor (10, 11) and a Non-Nucleoside Reverse Transcriptase Inhibitor (8) [Trovirdine Analogue belonging of the phenethyl thiazolyl thiourea class] connected through the "succinyl-glycine" spontaneously cleavable linker.
Asunto(s)
VIH-1/fisiología , Inhibidores de la Transcriptasa Inversa/síntesis química , Replicación Viral/efectos de los fármacos , Dimerización , VIH-1/efectos de los fármacos , Indicadores y Reactivos , Modelos Moleculares , Estructura Molecular , Piridinas/química , Inhibidores de la Transcriptasa Inversa/farmacologíaRESUMEN
A series of eleven heterodimers containing both a nucleoside analogue (d4U, d4T) and a non-nucleoside type inhibitor (Trovirdine analogue) were synthesized and evaluated for their ability to inhibit HIV replication. Unfortunately, the (N-3)d4U-Trovirdine conjugates (9a-e) and (N-3)d4T-Trovirdine conjugates (10a-f) were found to be inactive suggesting that the two individual inhibitor compounds do not bind simultaneously in their respective sites.
Asunto(s)
Didesoxinucleósidos/síntesis química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Piridinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Estavudina/síntesis química , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Didesoxinucleósidos/química , Didesoxinucleósidos/farmacología , Dimerización , Evaluación Preclínica de Medicamentos , VIH-1/efectos de los fármacos , VIH-1/enzimología , Humanos , Linfocitos/efectos de los fármacos , Linfocitos/enzimología , Linfocitos/virología , Piridinas/química , Piridinas/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Estavudina/química , Estavudina/farmacología , Células Tumorales Cultivadas , Zidovudina/farmacologíaRESUMEN
The target compounds 5-[N-(6-amino-hexyl)-acrylamide]-2',3'-didehydro-2',3'-dideoxy-uridine (12) and 5-[N-[5-(methoxycarbonyl)-pentyl]-acrylamide]-2',3'-didehydro-2',3'- dideoxy-uridine (15) were prepared by the palladium acetate-triphenylphosphine-catalyzed reaction of the 5'-O-acetyl-5-iodo-d4T analogue (3). These compounds 12 and 15 can be used to prepare nucleotide probes carrying fluorescent labels and were nevertheless screened for their anti-HIV activity. The biological data demonstrated that none of them were active against HIV-1.
Asunto(s)
Paladio/química , Estavudina/análogos & derivados , Estavudina/síntesis química , Uridina/análogos & derivados , Uridina/síntesis química , Catálisis/efectos de los fármacos , Línea Celular , Cromatografía en Capa Delgada , VIH-1/efectos de los fármacos , VIH-1/enzimología , VIH-1/fisiología , Humanos , Espectroscopía de Resonancia Magnética , Paladio/farmacología , ADN Polimerasa Dirigida por ARN/metabolismo , Espectroscopía Infrarroja por Transformada de Fourier , Estavudina/química , Estavudina/farmacología , Uridina/química , Uridina/farmacología , Zidovudina/farmacologíaRESUMEN
A series of beta-D-2',3'-didehydro-2',3'-dideoxy-nucleosides bearing a tether attached at the C-5 position and their beta-L-counterparts was synthesized. Their inhibitory activities against human immunodeficiency virus (HIV) were investigated and compared to establish relationship(s) between compound structure and their antiviral activity. No significant activity was observed for beta-D- and beta-L-modified nucleosides respectively 7a-c and 14a-c, but 7d and 14d exhibited a weak activity against HIV-1.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Didesoxinucleósidos/síntesis química , Didesoxinucleósidos/farmacología , VIH-1/efectos de los fármacos , Timidina/análogos & derivados , Línea Celular , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Timidina/síntesis químicaRESUMEN
A general strategy is reported for the preparation of C-5-methylamino- or methyldiamino-d4T analogues of "different sizes". Reactions of the 2',3'-didehydro-2',3'-dideoxy-C-5 hydroxymethyl precursor (7) with either polymethylene diamines (n = 6, 8, 10 and 12) or propargylamine proceed regioselectively via substitution reactions at the C-5 position of uracil. The compounds were evaluated for antiviral activity and cytotoxicity. No significant activity was observed for compounds 9, 11, and 13, but 10 and 12 exhibited a weak activity against HIV-1.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Estavudina/análogos & derivados , Estavudina/síntesis química , Fármacos Anti-VIH/farmacología , Línea Celular/efectos de los fármacos , Células Cultivadas , VIH-1/efectos de los fármacos , Humanos , ADN Polimerasa Dirigida por ARN/metabolismo , Estavudina/farmacologíaRESUMEN
This work reports the synthesis of 2',3'-didehydro-2',3'-dideoxy-thymidine analogues bearing several kinds of amino-linker arms at the C-5 position of the pyrimidine moiety. C-5 is an attractive position since a flexible chain may permit the triphosphates to be generated. The beta-D- and beta-L-d4T analogues were synthesized following a multi-step reaction from D-ribose and D-xylose, from D- and L-arabinose (towards an oxazoline ring) or from uridine and then were reacted with alkylene diamines.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/farmacología , Estavudina/síntesis química , Estavudina/farmacología , Línea Celular , VIH-1/efectos de los fármacos , Humanos , Pruebas de Sensibilidad MicrobianaRESUMEN
In an attempt to combine the human immunodeficiency virus type 1 (HIV-1)-inhibitory capacity of 2',3'-dideoxy-2',3'-didehydronucleoside analogues [nucleoside reverse transcriptase (RT) inhibitors; NRTI] and non-nucleoside RT inhibitors (NNRTI), we have designed, synthesized and evaluated for their anti-HIV activity several heterodimers of the general formula [d4T]-NH-(CH2)n-NH-[imidazo[1,5-b]pyridazine]. The synthesis of these heterodimers was conducted in three parts. The first part focused on the synthesis of the NRTI. The second part was devoted to the NNRTI and the NNRTI linked to appropriate spacers: [NNRTI]-NH-(CH2)n-NH2. In the third part, the condensation between the NRTI and the [NNRTI]-NH-(CH2)n-NH2 was performed. The in vitro inhibitory activities against HIV-1 of the [d4T]-NH-(CH2)n-NH-[imidazo[1,5-b]pyridazine] heterodimers were found to be comparable to that of d4T (stavudine) in HIV-infected cells. Moreover, the heterodimers were endowed with anti-HIV-2 activity and with anti-nevirapine-resistant HIV-1 activity. None of the heterodimers proved markedly cytotoxic to CEM-SS or MT-4 cells. There was not a clear trend toward antiviral potency on lengthening the methylene spacer in the [d4T]-NH-(CH2)n-NH-[imidazo[1,5-b]pyridazine] heterodimers.
Asunto(s)
Antivirales/síntesis química , VIH-1/efectos de los fármacos , Imidazoles/síntesis química , Piridazinas/síntesis química , Estavudina/análogos & derivados , Antivirales/farmacología , Línea Celular , Resistencia a Medicamentos , Inhibidores Enzimáticos , VIH-2/efectos de los fármacos , Imidazoles/farmacología , Estructura Molecular , Nevirapina/farmacología , Nucleósidos/síntesis química , Nucleósidos/farmacología , Conformación Proteica , Piridazinas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Estavudina/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
In response to the AIDS epidemic, the discovery of antiviral agents has been focused on the synthesis of nucleoside analogues. The basis moiety of these pyrimidine nucleosides were thieno and thiano[3,2-d]pyrimidine-2,4-dione possibly substituted on 7 position by methyl or aryl groups, 6,7-dihydrothieno[3,2-d]pyrimidin-4-one, bicyclic heterocycles including an uracil moiety. The first part of organic chemistry work has provided cyclic and acyclic N-nucleosides after adaptation of Vorbrüggen and Niedballa method. The carbohydrate fraction of these nucleosides included either a cyclic sugar yielding uridine, ARA U and IDU analogues or an hydroxylated chain that allowed access to aciclovir, ganciclovir and EBPU analogues. The second part has been devoted to functional arrangements beta-D-ribonucleoside respectively on carbohydrate and aglycon moieties carrying into reduction (synthesis of an unsaturated dideoxynucleoside, a d4T analogue) and amination reactions (cytidine analogue). Several compounds were tested against HIV1 in CEM cl 13 cell cultures, but none of them exhibited significant activity against this virus.
Asunto(s)
Antivirales/síntesis química , VIH-1/efectos de los fármacos , Nucleósidos de Pirimidina/síntesis química , Antivirales/farmacología , Humanos , Nucleósidos de Pirimidina/farmacologíaRESUMEN
Cyclization reaction of hydrazine with carbazole-2,3-methyl dicarboxylates gave 1,4-dioxo-1,2,3,4-tetrahydropyridazino[4,5-b]carbazoles. Chlorodehydroxylation provided 1,4-dichloropyridazino[4,5-b]carbazoles and nucleophilic substitution gave 1,4-dialkoxy pyridazino[4,5-b]carbazoles. These compounds were tested for cytotoxic activity against L1210 leukemia in mice.
Asunto(s)
Antineoplásicos/síntesis química , Carbazoles/síntesis química , Piridazinas/síntesis química , Animales , Carbazoles/farmacología , Carbazoles/toxicidad , Supervivencia Celular/efectos de los fármacos , Fenómenos Químicos , Química , Leucemia L1210/patología , Ratones , Mutágenos , Piridazinas/farmacología , Piridazinas/toxicidad , Salmonella typhimurium/efectos de los fármacos , Salmonella typhimurium/genéticaRESUMEN
Treatment of N-(2-furoyl)proline or N-thenoylprolines and N-(2-thenoyl)thiazolidine-4-carboxylic acid with acetic anhydride and dimethyl acetylenedicarboxylate gave 5-substituted derivatives of dimethyl 2,3-dihydro-1H-pyrrolizine-6,7-dicarboxylate and derivatives of dimethyl 5-(2-thienyl)pyrrolo[1,2-c]thiazole. Reduction of 2 with lithium aluminum hydride gave the diols 3a, 3b, 3c and 3d. These diols yielded the corresponding diacetates 4 by treatment with acetic anhydride. The bis(methylcarbamates) 5a, 5b, 5c, and 5d and bis(isopropylcarbamates) 6b and 6c are obtained with the appropriate isocyanates. The 1-substituted pyrrolizines were synthesized, the 1-acetoxy compounds 7b and 7c further transformed into 1-hydroxy and 1-oxo analogues. The action of hydrochloric acid on 1-acetoxy derivatives gave 3H-pyrrolizines. Evaluation of antileukemic activity was investigated on the leukemia L1210 in vivo, on several bis(alkylcarbamates). The compounds 5c and 5d show good antileukemic activity comparable with the mitomycin.