RESUMO
Novel L- and D-configuration 2',3'-dideoxy-4'-C-methyl-3'-oxacytidine and their 5-fluoro analogues have been synthesized from 1-benzyloxy-2-propanone and L-ascorbic acid in eight steps and evaluated for biological activity.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Animais , Antineoplásicos/síntese química , Antivirais/síntese química , Citidina/química , Ensaios de Seleção de Medicamentos Antitumorais , Leucemia L1210 , Espectroscopia de Ressonância Magnética , Testes de Sensibilidade Microbiana , Estrutura MolecularRESUMO
Various 2-halogen-substituted analogues (38, 39, 43 and 44), 3-halogen-substituted analogues (51 and 52), and 2',3'-dihalogen-substituted analogues (57-60) of 3-deazaadenosine and 3-halogen-substituted analogues (61 and 62) of 3-deazaguanosine have been synthesized as potential anticancer and/or antiviral agents. Among these compounds, 3-deaza-3-bromoguanosine (62) showed significant cytotoxicity against L1210, P388, CCRF-CEM and B16F10 cell lines in vitro, producing IC50 values of 3, 7, 9 and 7 microM, respectively. Several 3-deazaadenosine analogues (38, 51, 57 and 59) showed moderate to weak activity against hepatitis B virus.
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Guanosina/análogos & derivados , Guanosina/síntese química , Guanosina/farmacologia , Animais , Antineoplásicos/química , Bioquímica/métodos , Ensaios de Seleção de Medicamentos Antitumorais , Guanosina/química , HIV-1/efeitos dos fármacos , Halogênios/química , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Leucemia L1210 , Testes de Sensibilidade Microbiana , Células Tumorais CultivadasRESUMO
Novel L- and D-configuration dioxolane 5-azacytosine and 6-azathymine nucleosides have been synthesized and evaluated for biological activity. (-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-5-azacytosine (6) showed significant activity against HBV, whereas the D-configuration analogue (14) has been found to exhibit potent anti-HIV activity.
Assuntos
Citosina/análogos & derivados , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Timina/análogos & derivados , Animais , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antivirais/síntese química , Antivirais/farmacologia , Divisão Celular/efeitos dos fármacos , Citosina/síntese química , Citosina/farmacologia , Dioxolanos/síntese química , Dioxolanos/farmacologia , HIV-1/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Relação Estrutura-Atividade , Timina/síntese química , Timina/farmacologia , Células Tumorais Cultivadas/efeitos dos fármacosRESUMO
(2R,5S)-5-Amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]- 1,2,4-triazine-3(2H)-one (8) and (2R,5R)-5-amino-2-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,2,4-tr iazine-3(2H)-one (9) have been synthesized via a multi-step procedure from 6-azauridine. (2R,5S)-4-Amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]-1,3, 5-triazine-2(1H)-one (11) and (2R,5R)-4-amino-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]- 1,3,5-triazine-2(1H)-one (12), and the fluorosubstituted 3-deazanucleosides (19-24) have been synthesized by the transglycosylation of (2R,5S)-1-[2-[[(tert-butyldiphenylsilyl) oxy]methyl]-1,3-oxathiolan-5-yl] cytosine (2) with silylated 5-azacytosine and the corresponding silylated fluorosubstituted 3-deazacytosines, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by deprotection of the blocking groups. These compounds were tested in vitro for cytotoxicity against L1210, B16F10, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1 and HBV.
Assuntos
Antineoplásicos/síntese química , Antivirais/síntese química , Compostos Aza/síntese química , Compostos Heterocíclicos/química , Nucleosídeos de Pirimidina/síntese química , Tiofenos , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antivirais/química , Antivirais/farmacologia , Compostos Aza/química , Compostos Aza/farmacologia , Azauridina/química , Glicosilação , HIV-1/efeitos dos fármacos , Vírus da Hepatite B/efeitos dos fármacos , Humanos , Nucleosídeos de Pirimidina/química , Nucleosídeos de Pirimidina/farmacologia , Células Tumorais CultivadasRESUMO
2'-Deoxy-2'-methylene-6-azauridine (5) and 2'-deoxy-2'-methylene-6-azacytidine (8) have been synthesized via a multi-step procedure from 6-azauridine. 2'-Deoxy-2'-methylene-5-azacytidine (14a) and 2'-deoxy-2'-methylene-3-deazaguanosine (19a) and their corresponding alpha-anomers (14b and 19b) have been synthesized by the transglycosylation of 3',5'-O-(1,1,3,3- tetraisopropyldisiloxane-1,3-diyl)-2'-deoxy-2'-methyleneu ridine (12) with silylated 5-azacytosine and silylated N2-palmitoyl-3-deazaguanine, respectively, in the presence of trimethylsilyl trifluoromethanesulfonate as the catalyst in anhydrous dichloroethane, followed by separation of the isomers and deprotection of the blocking groups. These compounds were tested for cytotoxicity against B16F10, L1210, and CCRF-CEM tumor cell lines and for antiviral activity against HIV-1, HSV-1, and HSV-2.
Assuntos
Antineoplásicos/síntese química , Antivirais/síntese química , Compostos Aza/síntese química , Guanina/análogos & derivados , Guanina/síntese química , Pirimidinas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/toxicidade , Antivirais/química , Antivirais/farmacologia , Compostos Aza/química , Compostos Aza/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Guanina/química , Guanina/farmacologia , HIV-1/efeitos dos fármacos , Herpesvirus Humano 1/efeitos dos fármacos , Herpesvirus Humano 2/efeitos dos fármacos , Humanos , Indicadores e Reagentes , Leucemia L1210 , Camundongos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Células Tumorais CultivadasRESUMO
The antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) has been shown previously to be enhanced markedly by the co-administration of pyrimidine deoxyribonucleosides (Lin and Prusoff, Cancer Res 47: 394-397, 1987). In the present study, we examined the cellular mechanisms underlying the augmentation effect of thymidine, one of the pyrimidine deoxyribonucleosides. It was found that thymidine did not increase the cytotoxicity of BCNU for B16/F10 melanoma cells in vitro. Instead, thymidine appeared to produce modulatory actions on the immune system of the tumor-bearing mice. More than 40% of the BCNU/ thymidine-cured mice specifically rejected secondary rechallenge with the B16/F10 tumor. Furthermore, these cured mice developed extensive depigmentation of their natural black hair, suggesting immune reactions to normal melanocytes. When spleen cells from normal mice were treated with BCNU alone, their response to T-cell mitogen phytohemagglutinin was suppressed markedly. This suppression was ablated by co-administration of BCNU with thymidine. Such BCNU/thymidine treatment also augmented the activity of tumor-specific cytotoxic T-cells in tumor-bearing mice. Taken together, these results suggest that the enhanced antitumor activity of combined BCNU and thymidine may result from the action of thymidine on the immune effector mechanisms, which facilitate the development of antitumor immune responses in the presence of immunosuppression induced by BCNU.
Assuntos
Adjuvantes Imunológicos/farmacologia , Antineoplásicos Alquilantes/farmacologia , Carmustina/farmacologia , Timidina/farmacologia , Animais , Carmustina/administração & dosagem , Feminino , Hipersensibilidade Tardia , Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária , Melanoma Experimental/tratamento farmacológico , Camundongos , Camundongos Endogâmicos C57BL , Timidina/administração & dosagem , Células Tumorais CultivadasRESUMO
The antitumor activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) in mice previously was shown to be markedly enhanced by co-administration of thymidine. We have examined the cellular mechanisms underlying the augmentation effect of thymidine. It was found that thymidine did not increase the cytotoxicity of BCNU for B16/F10 melanoma or L1210 leukemia cells in vitro. Instead, thymidine appeared to augment the activity of tumor-specific cytotoxic T-cells in tumor-bearing mice, which specifically rejected a secondary challenge with the B16/F10 tumor. Thus, development of an antitumor immune response is facilitated by thymidine in BCNU-induced immunosuppressed mice. These preclinical studies suggested that combination therapy with alkylating agents and thymidine may be a more efficacious and less toxic anticancer therapy. The potential efficacy of the sequential administration of dacarbazine (DTIC), BCNU, and thymidine in patients with advanced malignant melanoma was investigated. As predicted from animal studies, sequential administration of DTIC, BCNU, and thymidine is a relatively nontoxic therapy for metastatic melanoma. This treatment induced durable responses in up to 35% of patients, and hence is superior to many commonly used toxic combination chemotherapies. The mechanism of action, although not well characterized, is thought to be mediated through protection of the cellular immune process, as well as organ function, from alkylating agent toxicity through modulation of DNA repair enzymes such as O(6)-alkylguanine-DNA alkyltransferase in normal tissue. Thus, thymidine is a biomodulator, which not only protects patients from hematologic, pulmonary, and hepatic toxicities associated with DTIC and BCNU chemotherapy, but also potentiates therapeutic efficacy.