RESUMO
Several small molecule CD4 mimics, which inhibit the interaction of gp120 with CD4, have been developed. Original CD4 mimics such as NBD-556, which has an aromatic ring, an oxalamide linker and a piperidine moiety, possess significant anti-HIV activity but with their hydrophobic aromatic ring-containing structures are poorly soluble in water. We have developed derivatives with a halopyridinyl group in place of the phenyl group, such as KKN-134, and found them to have excellent aqueous solubility. Other leads that were examined are YIR-821, a compound with a cyclohexane group in a spiro attachment to a piperidine ring and a guanidino group on the piperidine nitrogen atom, and its PEGylated derivative, TKB-002. YIR-821 and TKB-002 retain potent anti-HIV activity. Here, new CD4 mimics, in which the phenyl group was replaced by a halopyridinyl group with the halogen atoms in different positions, their derivatives without a cyclohexane group on the piperidine ring and their hybrid molecules with PEG units were designed and synthesized. Some of these compounds show significantly higher aqueous solubility with maintenance of certain levels of anti-HIV activity. The present data should be useful in the future design of CD4 mimic molecules.
Assuntos
Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , HIV-1/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Antígenos CD4/química , Relação Dose-Resposta a Droga , Inibidores da Fusão de HIV/síntese química , Inibidores da Fusão de HIV/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Proteínas Recombinantes/síntese química , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacologia , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Solubilidade , Relação Estrutura-AtividadeRESUMO
Several small molecule CD4 mimics have been reported previously as HIV-1 entry inhibitors, which block the interaction between the Phe43 cavity of HIV-1 gp120 and the host CD4. Known CD4 mimics such as NBD-556 possess significant anti-HIV activity but are less soluble in water, perhaps due to their hydrophobic aromatic ring-containing structures. Compounds with a pyridinyl group in place of the phenyl group in these molecules have been designed and synthesized in an attempt to increase the hydrophilicity. Some of these new CD4 mimics, containing a tetramethylpiperidine ring show significantly higher water solubility than NBD-556 and have high anti-HIV activity and synergistic anti-HIV activity with a neutralizing antibody. The CD4 mimic that has a cyclohexylpiperidine ring and a 6-fluoropyridin-3-yl ring has high anti-HIV activity and no significant cytotoxicity. The present results will be useful in the future design and development of novel soluble-type molecule CD4 mimics.
Assuntos
Antígenos CD4/química , Inibidores da Fusão de HIV/farmacologia , HIV-1/fisiologia , Mimetismo Molecular , Bibliotecas de Moléculas Pequenas/química , Anticorpos Neutralizantes/imunologia , Inibidores da Fusão de HIV/química , HIV-1/imunologia , Humanos , Solubilidade , Relação Estrutura-AtividadeRESUMO
CD4 mimics are small molecules that inhibit the interaction of gp120 with CD4. We have developed several CD4 mimics. Herein, hybrid molecules consisting of CD4 mimics with a long alkyl chain or a PEG unit attached through a self-cleavable linker were synthesized. In anti-HIV activity, modification with a PEG unit appeared to be more suitable than modification with a long alkyl chain. Thus, hybrid molecules of CD4 mimics, with PEG units attached through an uncleavable linker, were developed and showed high anti-HIV activity and low cytotoxicity. In investigation of pharmacokinetics in a rhesus macaque, a hybrid compound had a more effective PK profile than that of the parent compound, and intramuscular injection was a more useful administration route to maintain the high blood concentration of the CD4 mimic than intravenous injection. The presented hybrid molecules of CD4 mimics with a PEG unit would be practically useful when combined with a neutralizing antibody.
Assuntos
Antígenos CD4/química , Inibidores da Fusão de HIV/síntese química , Inibidores da Fusão de HIV/farmacologia , Polietilenoglicóis/química , Animais , Anticorpos Neutralizantes/química , Proteína gp120 do Envelope de HIV/efeitos dos fármacos , Inibidores da Fusão de HIV/farmacocinética , HIV-1/efeitos dos fármacos , Humanos , Injeções Intramusculares , Macaca mulatta , Modelos Moleculares , Mimetismo Molecular , Relação Estrutura-AtividadeRESUMO
Based on NOE experiments, the structure of naphthodipyranodione from Gentianaceae plants was revised to 1,2-dihydro-4H,6H,8H-naphto[1,2-d:4,5- c'd']dipyrano-4,8-dione. Naphthodipyranodione was assumed to be formed by the degradation of gentiopicroside by enzymatic hydrolysis at low water -concentration. The degradation pathway was a unique domino-reaction triggered by enzymatic hydrolysis. Naphthodipyranodione may become an index compound for the drying and/or fermenting procedure of Gentian root.