RESUMO
A series of novel 2-phenyl-benzo[d]oxazole-7-carboxamide derivatives were designed, synthesized and evaluated for their in vitro inhibitory activities against Staphylococcus aureus Sortase A with known Sortase A inhibitor pHMB as positive compound (IC50=130µM). Most compounds exhibited excellent inhibitory activity (IC50=19.8-184.2µM). Structure-activity relationship studies demonstrated that substitution at 7-position and 2-position of benzoxazole had great influence on the activities. Specifically, the substituent at 7-position is indispensable for inhibitory activity. The molecular docking studies revealed the i-butyl amide group went towards the ß6/ß7 loop-ß8 substructure of the protein and the benzoxazole core lied in a hydrophobic pocket composed of Ala118, Val166, Val168, Val169 and Ile182, shaping the whole molecule into a L-shape mode to be recognized by Sortase A.
Assuntos
Amidas/química , Aminoaciltransferases/antagonistas & inibidores , Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Staphylococcus aureus/enzimologia , Amidas/síntese química , Amidas/metabolismo , Amidas/farmacologia , Aminoaciltransferases/metabolismo , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Cisteína Endopeptidases/metabolismo , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Oxazóis/química , Ligação Proteica , Estrutura Terciária de Proteína , Eletricidade Estática , Relação Estrutura-AtividadeRESUMO
Tumor hypoxia is the necessary process in the development of solid tumors, which is the key factor for drug resistance, recurrence, attack and shift of tumor. Hypoxic tumor cells have a certain extent of tolerance to radiation and chemotherapy. Tumor hypoxia is an important target for medication therapy. In the recent years, the bioreductive drugs targeted tumor hypoxia has made great process in the treatment of tumors. The latest advances of bioreductive drugs targeted hypoxia were reviewed in this paper.
Assuntos
Antineoplásicos , Hipóxia , Neoplasias/tratamento farmacológico , Substâncias Redutoras , Antineoplásicos/uso terapêutico , Hipóxia Celular , Humanos , Quinonas/uso terapêutico , Substâncias Redutoras/uso terapêuticoRESUMO
Two analogues of cryptophycin were synthesized and biologically evaluated for their in-vitro cytotoxicities against several solid tumors and leukemia cell lines. The results revealed that both analogues exhibited a broad range of cytotoxic activity with observed IC(50 )values in the muM-range, and compound 4 was more effective than compound 3 in most assays studied.
