RESUMO
An enantioselective synthesis of a putative lipiarmycin aglycon was accomplished and features: 1)â Brown's enantioselective alkoxyallylboration and allylation of aldehydes, 2)â chain elongation by iterative Horner-Wadsworth-Emmons olefination, 3)â Evans' aldol reaction and 4)â an ene-diene ring-closing metathesis. A neighboring-group-assisted chemoselective reductive desilylation was uncovered in this study and was instrumental to the realization of the present synthesis.
Assuntos
Aminoglicosídeos/síntese química , Aminoglicosídeos/química , Fidaxomicina , EstereoisomerismoRESUMO
The small molecule, 2-(1-hydroxyundecyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione (A12B4C3), is a potent inhibitor of the phosphatase activity of human polynucleotide kinase/phosphatase (PNKP) in vitro. Kinetic analysis revealed that A12B4C3 acts as a noncompetitive inhibitor, and this was confirmed by fluorescence quenching, which showed that the inhibitor can form a ternary complex with PNKP and a DNA substrate, i.e. A12B4C3 does not prevent DNA from binding to the phosphatase DNA binding site. Conformational analysis using circular dichroism, UV difference spectroscopy, and fluorescence resonance energy transfer all indicate that A12B4C3 disrupts the secondary structure of PNKP. Investigation of the potential site of binding of A12B4C3 to PNKP using site-directed mutagenesis pointed to interaction between Trp(402) of PNKP and the inhibitor. Cellular studies revealed that A12B4C3 sensitizes A549 human lung cancer cells to the topoisomerase I poison, camptothecin, but not the topoisomerase II poison, etoposide, in a manner similar to small interfering RNA against PNKP. A12B4C3 also inhibits the repair of DNA single and double strand breaks following exposure of cells to ionizing radiation, but does not inhibit two other key strand-break repair enzymes, DNA polymerase beta or DNA ligase III, providing additional evidence that PNKP is the cellular target of the inhibitor.
Assuntos
Enzimas Reparadoras do DNA/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Piperidinas/farmacologia , Pirróis/farmacologia , Trifosfato de Adenosina/metabolismo , Antineoplásicos Fitogênicos/farmacologia , Sítios de Ligação , Camptotecina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Dicroísmo Circular , DNA Ligase Dependente de ATP , DNA Ligases/antagonistas & inibidores , DNA Ligases/metabolismo , DNA Polimerase beta/antagonistas & inibidores , DNA Polimerase beta/metabolismo , Reparo do DNA/efeitos dos fármacos , Enzimas Reparadoras do DNA/química , Enzimas Reparadoras do DNA/genética , Etoposídeo/farmacologia , Transferência Ressonante de Energia de Fluorescência , Humanos , Neoplasias Pulmonares/metabolismo , Mutagênese Sítio-Dirigida , Fosfotransferases (Aceptor do Grupo Álcool)/química , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Espectroscopia Fotoeletrônica , Proteínas de Ligação a Poli-ADP-Ribose , Conformação Proteica , Pirróis/química , Radiossensibilizantes/farmacologia , Células Tumorais Cultivadas , Proteínas de XenopusRESUMO
Tagging along: a system for phase-switch synthesis has been developed. The boronic acid functionality is used as a phase tag that complexes to sorbitol and facilitates compound transfer from an organic solvent to water at high pH. The phase tag can then be used in a productive reaction step to generate targeted products, thereby eliminating purification by silica gel chromatography.
RESUMO
Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition, and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 was able to cause a sustained reduction of LPA levels in plasma in vivo and was shown to be efficacious in a bleomycin-induced pulmonary fibrosis model in mice and in reducing extracellular matrix deposition in the lung while also reducing LPA 18:2 content in bronchoalveolar lavage fluid. Compound 11 is currently being evaluated in an exploratory phase 2a study in idiopathic pulmonary fibrosis patients.