RESUMO
An approach for designing bioactive small molecules has been developed in which de novo structure-based ligand design (SBLD) was focused on regions of chemical space accessible using a diversity-oriented synthetic approach. The approach was exploited in the design and synthesis of a focused library of platensimycin analogues in which the complex bridged ring system was replaced with a series of alternative ring systems. The affinity of the resulting compounds for the C163Q mutant of FabF was determined using a WaterLOGSY competition binding assay. Several compounds had significantly improved affinity for the protein relative to a reference ligand. The integration of synthetic accessibility with ligand design enabled focus to be placed on synthetically-accessible regions of chemical space that were relevant to the target protein under investigation.
Assuntos
Acetiltransferases/antagonistas & inibidores , Adamantano/farmacologia , Aminobenzoatos/farmacologia , Anilidas/farmacologia , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Proteínas de Escherichia coli/antagonistas & inibidores , Acetiltransferases/genética , Acetiltransferases/metabolismo , Adamantano/síntese química , Adamantano/química , Aminobenzoatos/síntese química , Aminobenzoatos/química , Anilidas/síntese química , Anilidas/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Ácido Graxo Sintase Tipo II/antagonistas & inibidores , Ácido Graxo Sintase Tipo II/genética , Ácido Graxo Sintase Tipo II/metabolismo , Ligantes , Modelos Moleculares , Conformação Molecular , Relação Estrutura-AtividadeRESUMO
Colchicine was modified at the 10-OCH(3) position of the C-ring by reaction with heterocyclic amines or commercially available amines to afford a library of target colchicinoids in high yields (62-99%). Molecular modeling revealed that the incorporation of the linker groups led to a reduction in entropy and therefore binding affinity when compared with colchicine. Some colchicinoids were shown to be equicytotoxic with colchicine when evaluated in the DLD-1 colon cancer cells and retained activity in resistant A2780AD or HeLa cells with mutant Class III ß-tubulin. Importantly, unlike colchicine, the analogues in this study are amenable for prodrug derivatisation and with potential for tumor-selective delivery.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Colchicina/farmacologia , Pró-Fármacos/farmacologia , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/síntese química , Colchicina/química , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Modelos Moleculares , Estrutura Molecular , Pró-Fármacos/síntese química , Pró-Fármacos/química , Relação Estrutura-AtividadeRESUMO
[structure: see text]. The first enantioselective total synthesis of 1-epi-pathylactone A, 3, has been accomplished using a PhI(OAc)2-mediated domino reaction as a key step. No diastereomeric separation was required throughout the whole synthetic scheme presented in this paper. Comparison of 1H and 13C NMR spectral data of the synthetic product with the reported spectral data of natural pathylactone A, coupled with an X-ray crystallographic analysis, led to the conclusion that the C1 configuration in the original paper was erroneously ascribed to (R).
