RESUMO
Our previous studies reveal that indolizinoquinolinedione scaffold is a base to develop novel DNA topoisomerase IB (TOP1) catalytic inhibitors. In this work, twenty-three novel indolizinoquinolinedione derivatives were synthesized. TOP1-mediated relaxation, nicking and unwinding assays revealed that three fluorinated derivatives 26, 28 and 29, and one N,N-trans derivative 46 act as TOP1 catalytic inhibitors with higher TOP1 inhibition (++++) than camptothecin (+++) and without TOP1-mediated unwinding effect. MTT assay against five human cancer cell lines indicated that the highest cytotoxicity is 20 for CCRF-CEM cells, 25 for A549 and DU-145â¯cells, 26 for HCT116â¯cells, and 33 for Huh7 cells with GI50 values at nanomolar range. The drug-resistant cell assay indicated that compound 26 may mainly act to TOP1 in cells and are less of Pgp substrates. Flow cytometric analysis showed that compounds 26, 28 and 29 can obviously induce apoptosis of HCT116â¯cells. Moreover, the structure-activity relationship (SAR) of indolizinoquinolinedione derivatives was analyzed.
Assuntos
Antineoplásicos/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Indolizinas/farmacologia , Quinolonas/farmacologia , Inibidores da Topoisomerase I/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Biocatálise , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indolizinas/síntese química , Indolizinas/química , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase I/síntese química , Inibidores da Topoisomerase I/química , Células Tumorais CultivadasRESUMO
In our previous research, 9-bromo indolizinoquinoline-5,12-dione 1 has been found to be a good anti-MRSA agent. However, it had very low bioavailability in vivo possibly due to its low solubility in water. In order to obtain the derivatives with higher anti-MRSA activity and good water solubility, twenty eight bromo-substituted indolizinoquinoline-5,12-dione derivatives were synthesized in the present study. The antibacterial activity of the synthesized compounds was evaluated against one gram-negative and some gram-positive bacterial strains including 100 clinical MRSA strains. The UV assays were carried out to determine the solubility of six active compounds 16, 21, 23 and 27-29. The most potent compound 28 exhibited strong activity against clinical MRSA strains with both MIC50 and MIC90 values lower than 7.8 ng/mL. Compound 27 had good water solubility of 1.98 mg/mL and strong activity against clinical MRSA strains with MIC50 value of 63 ng/mL and MIC90 value of 125 ng/mL, 16-fold higher than that of Vancomycin.