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1.
Eur J Med Chem ; 67: 447-53, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23920246

RESUMEN

We have synthesized a series of novel 2-pyridone derivatives with 1,2,3-triazole and evaluated their anti-tumor activities in vitro. The bioassays showed that the majority of the resultant compounds exerted inhibitory effects on six human cancer cell lines to various extents. In particular, compound 10k showed the best anti-tumor activities (IC50 values of A549, HeLa and SW480 cancer cell lines were 0.86 ± 0.17 µM, 0.54 ± 0.23 µM and 0.21 ± 0.13 µM, respectively).


Asunto(s)
Antineoplásicos/farmacología , Diseño de Fármacos , Piridonas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Estructura Molecular , Piridonas/síntesis química , Piridonas/química , Relación Estructura-Actividad
2.
J Med Chem ; 56(3): 685-99, 2013 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-23356786

RESUMEN

A series of novel cyclopropylamide analogues of combretastatin-A4 (CA-4) were designed and synthesized. Most of them had significant in vitro antiproliferative activities, particularly for compounds 7i4, 7c4, 8a4, and 8c4. Moreover, compound 8c4 was also equally potent against paclitaxel resistant cancer cells. Interestingly, the novel cyclopropylamide analogues had different binding mechanisms from CA-4. Instead of inhibiting tubulin polymerization, these CA-4 derivatives were able to stimulate tubulin polymerization. Flow cytometry revealed that compound 8c4 arrested A549 cancer cells in the G2/M phase and resulted in cellular apoptosis. Further immunofluorescence assays revealed that compound 8c4 induced mitotic arrest in A549 cells through disrupting microtubule dynamics. In addition, compound 8c4 also effectively inhibited the tumor growth in the A549 xenograft model without causing significant loss of body weight. Compound 8c4 represents a novel class of microtubule-stabilizing agent and can be used as a promising lead for the development of new antitumor agents.


Asunto(s)
Diseño de Fármacos , Microtúbulos/efectos de los fármacos , Estilbenos/química , Estilbenos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estilbenos/síntesis química , Relación Estructura-Actividad
3.
Bioorg Med Chem Lett ; 21(11): 3381-3, 2011 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-21515044

RESUMEN

A series of ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylates were prepared through the metal-catalyzed domino reaction of alkylidene malonates and 1,4-butynediol under a one-pot reaction condition at room temperature. Their in vitro anti-proliferative activities were subsequently evaluated in A549, QGY and HeLa cells. The majority of the compounds showed potent anti-tumor activity against HeLa cells. In particular, compound 3l was the most potent compound with IC(50) value of 5.4 µM. For the first time, the X-ray structure of the anti-tumor ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylates is determined.


Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/farmacología , Furanos/síntesis química , Piranos/síntesis química , Antineoplásicos/química , Ácidos Carboxílicos/química , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Furanos/química , Furanos/farmacología , Células HeLa , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Piranos/química , Piranos/farmacología
4.
J Med Chem ; 53(2): 660-8, 2010 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-20000776

RESUMEN

A series of novel 2-pyridone derivatives were synthesized and evaluated for their antihepatitis B virus (HBV) activity and cytotoxicity in vitro. Moderate to good activity against HBV DNA replication was observed in these 2-pyridone analogues. The most active compounds were 5d and 6l, with good inhibitory activity against HBV DNA replication (IC(50) = 0.206 and 0.12 microM, respectively) and remarkable high selectivity (selectivity indexes of >532 and 467, respectively). A pharmacophore model of the synthesized compounds was proposed by the GASP program. The pharmacophore model consists of three hydrophobic points, four HBA points, and one HBD point. The 2-pyridone derivatives represent a novel class of HBV inhibitors, which are worth further optimization.


Asunto(s)
Antivirales/síntesis química , Virus de la Hepatitis B/efectos de los fármacos , Piridonas/síntesis química , Antivirales/farmacología , Línea Celular , Replicación del ADN/efectos de los fármacos , Diseño de Fármacos , Humanos , Modelos Moleculares , Piridonas/farmacología , Relación Estructura-Actividad
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