RESUMO
In vivo anti-HIV efficacy of (+)-calanolide A has been evaluated in a hollow fiber mouse model. It was demonstrated that the compound was capable of suppressing virus replication in two distinct and separate physiologic compartments (i.p. and s.c.) following oral or parenteral administration on a once- or twice-daily treatment schedule. A synergistic effect was observed for the combination of (+)-calanolide A and AZT.
Assuntos
Fármacos Anti-HIV/farmacologia , Cumarínicos/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular , Células Cultivadas , Cumarínicos/administração & dosagem , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Proteína do Núcleo p24 do HIV/sangue , Proteína do Núcleo p24 do HIV/efeitos dos fármacos , Transcriptase Reversa do HIV/efeitos dos fármacos , Transcriptase Reversa do HIV/metabolismo , Humanos , Macrófagos/efeitos dos fármacos , Camundongos , Piranocumarinas , Fatores de Tempo , Zidovudina/farmacologiaRESUMO
The three chromanone derivatives, (+)-, (-)-, and (+/-)-12-oxocalanolide A (2), were evaluated for in vitro antiviral activities against HIV and simian immunodeficiency virus (SIV). The compounds were determined to be inhibitors of HIV-1 reverse transcriptase (RT) and exhibited activity against a variety of viruses selected for resistance to other HIV-1 nonnucleoside RT inhibitors. They are the first reported calanolide analogues capable of inhibiting SIV.
Assuntos
Fármacos Anti-HIV/farmacologia , Cromonas/síntese química , Cumarínicos/química , Cumarínicos/síntese química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Síndrome da Imunodeficiência Adquirida/virologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Linhagem Celular , Cromonas/química , Cromonas/farmacologia , Cumarínicos/farmacologia , Desenho de Fármacos , HIV-1/enzimologia , HIV-1/isolamento & purificação , Humanos , Técnicas In Vitro , Leucócitos/virologia , Macrófagos/virologia , Monócitos/virologia , Piranocumarinas , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
(+)-Calanolide A is a potent inhibitor of reverse transcriptase from human immunodeficiency virus type 1 (HIV-1), which was isolated from an extract of Calophyllum lanigerum, along with seven related compounds. In order to examine the structure-activity relationships of the trans-10,11-dimethyldihydropyran-12-ol ring (designated ring C), a series of structural analogues were prepared and evaluated using a whole cell cytopathicity assay (XTT). Removal of the 10-methyl group resulted in decreased activity, with only one epimer exhibiting anti-HIV activity. Substituting the 10-methyl group with an ethyl chain maintained anti-HIV activity, with only a 4-fold reduction in potency relative to racemic calanolide A. Substitution of the 10-methyl group with an isopropyl moiety completely eliminated the anti-HIV activity. Addition of an extra methyl group at either the 10- or 11-position maintained the basic stereochemical features of the parent calanolide system while removing the chirality at the respective carbon, but resulted in decreased activity relative to calanolide A. In all the above examples, analogues containing a cis relationship between the 10- and 11-alkyl moieties were completely devoid of activity. Synthetic intermediates in which the 12-hydroxyl group was in the ketone oxidation state exhibited suppressing anti-HIV activity, with EC50 values only 5-fold less potent than that of calanolide A for both the 10,11-cis (6) and -trans (5) series. These ketones represent the first derivatives in the calanolide series to exhibit anti-HIV activity while not containing a 12-hydroxyl group. Likewise, ketone derivative 6 was the first example of a compound in the calanolide series having a cis relationship between the 10- and 11-methyl groups found to exhibit anti-HIV activity. Analogues which showed anti-HIV activity in the CEM-SS cytoprotection assay were further confirmed to be inhibitors of HIV-1 reverse transcriptase.
Assuntos
Fármacos Anti-HIV/química , Cumarínicos/química , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/metabolismo , Cumarínicos/farmacologia , Transcriptase Reversa do HIV/metabolismo , HIV-1/enzimologia , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Piranocumarinas , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/farmacologia , Células Tumorais CultivadasRESUMO
The anti-HIV agent (+/-)-calanolide A (1) has been synthesized in a five-step approach starting with phloroglucinol [-->5-->6-->11-->18-->(+/-)-1], which includes Pechmann reaction, Friedel-Crafts acylation, chromenylation with 4,4-dimethoxy-2-methylbutan-2-ol, cyclization, and Luche reduction. Cyclization of chromene 11 to chromanone 18 was achieved by employing either acetaldehyde diethyl acetal or paraldehyde in the presence of trifluoroacetic acid and pyridine or PPTS. Luche reduction of chromanone 18 at lower temperature preferably yielded (+/-)-1. Reduction of chromone 12, synthesized by Kostanecki-Robinson reaction from chromene 11, failed to afford (+/-)-1. The synthetic (+/-)-1 has been chromatographically resolved into its optically active forms, (+)- and (-)-1. The anti-HIV activities for synthetic (+/-)-1, as well as resultant (+)- and (-)-1, have been determined. Only (+)-1 accounted for anti-HIV activity, which was similar to the data reported for the natural product, and (-)-1 was inactive.
