RESUMEN
A novel series of barbiturate and thiobarbiturate analogs of 2-benzoyl-3-methyl-5-oxo-5H-furo[3,2-g]chromene-6-carbaldehydes (3a-g and 4a-d, respectively) and 6-methyl-4,8-dioxo-4,8-dihydropyrano[3,2-g]chromenes (7a-c), were synthesized and evaluated for their antitubercular activities against Mycobacterium tuberculosis H37RV, and cytotoxicity (CC(50)) in the VERO cell MABA assay. The results indicate that the furanochromene series of compounds (3a-g and 4a-d) showed only weak to moderate antitubercular activity. However, the pyranochromene analog 7b showed good antitubercular activity (IC(90): 5.9µg/mL) and cytotoxicity (CC(50): 14.27µg/mL). The antitubercular activity of 7b was superior to the antituberculosis drug, pyrazinamide (PZA; IC(90): >20µg/mL). Analog 7b was considered to be a lead compound for subsequent structural optimization.
Asunto(s)
Antituberculosos/síntesis química , Barbitúricos/química , Cromonas/síntesis química , Cumarinas/síntesis química , Tiobarbitúricos/química , Animales , Antituberculosos/química , Antituberculosos/toxicidad , Barbitúricos/síntesis química , Barbitúricos/toxicidad , Chlorocebus aethiops , Cromonas/química , Cromonas/toxicidad , Cumarinas/química , Cumarinas/toxicidad , Pruebas de Sensibilidad Microbiana , Mycobacterium tuberculosis/efectos de los fármacos , Tiobarbitúricos/síntesis química , Tiobarbitúricos/toxicidad , Células VeroRESUMEN
A series of substituted (Z)-5-(N-benzylindol-3-ylmethylene)imidazolidine-2,4-dione (3) analogs structurally related to aplysinopsin, and that incorporate a variety of substituents in both the indole and N-benzyl moieties have been synthesized under microwave irradiation and conventional heating methods These analogs were evaluated for their anti-proliferative activity against MCF-7 and MDA-231 breast cancer cell lines, and A549 and H460 lung cancer cell lines. Two analogs, 3f and 3j had IC(50) values of 4.4 and 5.2microM, respectively, compared to 5-fluorouracil (IC(50)=15.2microM) against MCF-7 cells.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales/métodos , Imidazolidinas/farmacología , Triptófano/análogos & derivados , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Línea Celular Tumoral , Diseño de Fármacos , Humanos , Imidazolidinas/síntesis química , Indoles/química , Concentración 50 Inhibidora , Relación Estructura-Actividad , Triptófano/síntesis química , Triptófano/química , Triptófano/farmacologíaRESUMEN
Use of ionizing radiation is essential for the management of many human cancers, and therapeutic hyperthermia has been identified as a potent radiosensitizer. Radiation therapy combined with adjuvant hyperthermia represents a potential tool to provide outstanding local-regional control for refractory disease. (Z)-(+/-)-2-(N-Benzylindol-3-ylmethylene)quinuclidin-3-ol (2) and (Z)-(+/-)-2-(N-benzenesulfonylindol-3-ylmethylene)quinuclidin-3-ol (4) were initially identified as potent thermal sensitizers that could lower the threshold needed for thermal sensitivity to radiation treatment. To define the structural requirements of the molecule that are essential for thermal sensitization, we have synthesized and evaluated a series of (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one (9), and (Z)-(+/-)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol (10) analogs that incorporate a variety of substituents in both the indole and N-benzyl moieties. These systematic structure-activity relationship (SAR) studies were designed to further the development and optimization of potential clinically useful thermal sensitizing agents. The most potent analog was compound 10 (R(1)=H, R(2)=4-Cl), which potently inhibited (93% inhibition at 50 microM) the growth of HT-29 cells after a 41 degrees C/2h exposure.
