RESUMO
BACKGROUND: Since its isolation in 1970, and discovery of its potent inhibitory activity on T-cell proliferation, cyclosporin A (CsA) has been shown to play a significant role in diverse fields of biology. Furthermore, chemical modification of CsA has led to analogs with distinct biological activities associated with its protein receptor family, cyclophilins. SCOPE OF REVIEW: This review systematically collates the synthetic chemistry performed at each of the eleven amino acids, and provides examples of the utility of such transformations. The various modifications of CsA are traced from early, modest chemistry performed at the unique Bmt residue, through the remarkable use of a polyanion enolate that can be stereoselectively manipulated, and onto application of more recently developed olefin metathesis chemistry to prepare new CsA derivatives with unexpected biological activity. MAJOR CONCLUSIONS: The myriad biological activities of CsA and its synthetic derivatives have inspired the development of new approaches to modify the CsA ring. In turn, these new CsA derivatives have served as tools in the discovery of new roles for cyclophilins. GENERAL SIGNIFICANCE: This review provides information on the types of cyclosporin derivatives that are available to the many biologists working in this field, and should be of value to the medicinal chemist trying to discover drugs based on CsA. This article is part of a Special Issue entitled Proline-directed foldases: Cell signaling catalysts and drug targets.
Assuntos
Ciclosporinas/síntese química , Ciclosporinas/química , HumanosRESUMO
Cyclophilins (Cyps) are ubiquitous proteins that effect the cis-trans isomerization of Pro amide bonds, and are thus crucial to protein folding. CypA is the most prevalent of the ~19 human Cyps, and plays a crucial role in viral infectivity, most notably for HIV-1 and HCV. Cyclophilins have been shown to play key roles in effective replication of a number of viruses from different families. A drug template for CypA inhibition is cyclosporine A (CsA), a cyclic undecapeptide that simultaneously binds to both CypA and the Ca(2+)-dependent phosphatase calcineurin (CN), and can attenuate immune responses. Synthetic modifications of the CsA scaffold allows for selective binding to CypA and CN separately, thus providing access to novel, non-immunosuppressive antiviral agents.
Assuntos
Antivirais/química , Antivirais/farmacologia , Ciclofilinas/antagonistas & inibidores , Vírus/efeitos dos fármacos , Sítios de Ligação , Ciclosporina/química , Modelos Moleculares , Replicação Viral/efeitos dos fármacos , Vírus/genéticaRESUMO
An efficient synthesis of [D-lysine](8)cyclosporin A has been developed. Several analogs of [D-lysine](8)cyclosporin A have been synthesized and show promising anti-HCV activity, particularly compounds 39 and 43, which each exhibit an anti-HCV EC(50)<200 nM, and are each ≥50-fold less immunosuppressive than cyclosporin A.
Assuntos
Antivirais/síntese química , Antivirais/farmacologia , Ciclosporina/síntese química , Ciclosporina/farmacologia , Hepacivirus/efeitos dos fármacos , Cristalografia por Raios X , Modelos MolecularesRESUMO
Novel 2,3-diarylindoles bearing an amine substituent at the indole 5- and 6-positions have been synthesized and evaluated as anticoccidial agents in both in vitro and in vivo assays. Both subnanomolar in vitro activity and broad spectrum in vivo potency were detected for several compounds, particularly compound 27.
Assuntos
Coccidiostáticos/síntese química , Indóis/síntese química , Animais , Coccidiose/tratamento farmacológico , Coccidiose/enzimologia , Coccidiose/parasitologia , Coccidiostáticos/farmacologia , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Eimeria tenella/efeitos dos fármacos , Eimeria tenella/enzimologia , Eimeria tenella/crescimento & desenvolvimento , Indóis/farmacologia , Aves Domésticas/parasitologia , Piridinas/síntese químicaRESUMO
Novel 5,6-diarylimidazo[2,1-b][1,3]thiazoles bearing an amine substituent at the imidazothiazole 2-position have been synthesized and evaluated as anticoccidial agents in both in vitro and in vivo assays. Both subnanomolar in vitro activity and broad spectrum in vivo potency were detected for several compounds, particularly compound 10.
Assuntos
Coccidiostáticos/síntese química , Coccidiostáticos/farmacologia , Imidazóis/síntese química , Imidazóis/farmacologia , Tiazóis/síntese química , Tiazóis/farmacologia , Animais , Coccidiostáticos/química , Técnicas de Química Combinatória , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Eimeria/efeitos dos fármacos , Imidazóis/química , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Tiazóis/químicaRESUMO
Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Recently, we reported the synthesis and biological activity of potent imidazo[1,2-a]pyridine anticoccidial agents. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we report the synthesis and anticoccidial activity of a second set of such compounds, focusing on derivatization of the amine side chain at the imidazopyridine 7-position. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.
Assuntos
Coccidiostáticos/síntese química , Coccidiostáticos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Animais , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Eimeria/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Coccidiosis is the major cause of morbidity and mortality in the poultry industry. Protozoan parasites of the genus Eimeria invade the intestinal lining of the avian host causing tissue pathology, poor weight gain, and in some cases mortality. Resistance to current anticoccidials has prompted the search for new therapeutic agents with potent in vitro and in vivo activity against Eimeria. Antiparasitic activity is due to inhibition of a parasite specific cGMP-dependent protein kinase (PKG). In this study, we present the synthesis and biological activity of imidazo[1,2-a]pyridine anticoccidial agents. From this series, several compounds showed subnanomolar in vitro activity and commercial levels of in vivo activity. However, the potential genotoxicity of these compounds precludes them from further development.
Assuntos
Coccidiostáticos/síntese química , Coccidiostáticos/farmacologia , Eimeria/efeitos dos fármacos , Imidazóis/síntese química , Imidazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Animais , Disponibilidade Biológica , Coccidiostáticos/química , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Eimeria/fisiologia , Imidazóis/química , Concentração Inibidora 50 , Piridinas/químicaRESUMO
Compounds 10a (IC50 110 pM) and 21 (IC50 40 pM) are the most potent inhibitors of Eimeria tenella cGMP-dependent protein kinase activity reported to date and are efficacious in the in vivo antiparasitic assay when administered to chickens at 12.5 and 6.25 ppm levels in the feed. However, both compounds are positive in the Ames microbial mutagenesis assay which precludes them from further development as antiprotozoal agents in the absence of negative lifetime rodent carcinogenicity studies.