RESUMEN
To evaluate the influence of stereochemistry on biological activities of cis-cyclopropyl combretastatin A4 (CA4) analogues, we have prepared several cyclopropyl compounds in their pure enantiomeric forms. The key reactions in our synthesis are the cyclopropanation of a (Z)-alkenylboron compound bearing a chiral auxiliary, and the cross-coupling of both enantiomeric cyclopropyl trifluoroborate salts with aryl and olefinic halides. Three pairs of cis-cyclopropyl CA4 analogues were evaluated for their potential antivascular activities. The diarylcyclopropyl compounds with SR-configuration (-)-1b, (-)-2b and the cyclopropylvinyl enantiomer (+)-3a with RR-configuration were the most potent tubulin polymerization inhibitors. A correlation was noted between anti-tubulin activity and rounding up activity of endothelial cells. The cytotoxic activity on B16 melanoma cells was in the submicromolar range for most compounds, but unlike the anti-tubulin activity, there was no difference in cytotoxic activity between racemic and enantiomerically pure forms for the three series of compounds. Molecular docking studies within the colchicine binding site of tubulin were in good agreement with the tubulin polymerization inhibitory data and confirmed the importance of the configuration of the synthesized cis-cyclopropyl CA4 analogues for potential antivascular activities.
Asunto(s)
Ciclopropanos/química , Estilbenos/química , Moduladores de Tubulina/síntesis química , Animales , Sitios de Unión , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Colchicina , Ciclopropanos/síntesis química , Ciclopropanos/toxicidad , Evaluación Preclínica de Medicamentos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Ratones , Simulación del Acoplamiento Molecular , Estereoisomerismo , Relación Estructura-Actividad , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/química , Moduladores de Tubulina/toxicidadRESUMEN
A series of combretastatin A4 (CA4) analogues with a lactam or lactone ring fused to the trimethoxyphenyl or the B-phenyl moiety were synthesized in an efficient and stereoselective manner by using a domino Heck-Suzuki-Miyaura coupling reaction. The vascular-disrupting potential of these conformationally restricted CA4 analogues was assessed by various inâ vitro assays: inhibition of tubulin polymerization, modification of endothelial cell morphology, and disruption of endothelial cell cords. Compounds were also evaluated for their growth inhibitory effects against murine and human tumor cells. B-ring-constrained derivatives that contain an oxindole ring (in contrast to compounds with a benzofuranone ring) as well as analogues bearing a six-membered lactone core fused to the trimethoxyphenyl ring are endowed with significant biological activity. The most potent compound of this series (oxindole 9 b) is of particular interest, as it combines chemical stability and a biological activity profile characteristic of a vascular-disrupting agent.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Células Endoteliales/efectos de los fármacos , Compuestos Heterocíclicos/farmacología , Estilbenos/farmacología , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Catálisis , Línea Celular Tumoral , Células Endoteliales/metabolismo , Células Endoteliales/patología , Compuestos Heterocíclicos/química , Humanos , Ratones , Paladio/química , Estilbenos/síntesis química , Estilbenos/química , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismoRESUMEN
Two series of 2-aroyltrimethoxyindoles were designed to investigate the effects of the replacement of the trimethoxyphenyl ring of phenstatin with a trimethoxyindole moiety. These compounds were efficiently prepared through a domino palladium-catalyzed sequence from 2-gem-dibromovinylanilines substituted by three methoxy groups and arylboronic acids under carbon monoxide atmosphere. These novel heterocyclic combretastatin A4 analogues were evaluated for their cell growth inhibitory properties and their ability to inhibit the tubulin polymerization.
Asunto(s)
Descubrimiento de Drogas/métodos , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Indoles/química , Indoles/farmacología , Estilbenos/química , Estilbenos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Ratones , Multimerización de Proteína/efectos de los fármacos , Estructura Cuaternaria de Proteína , Tubulina (Proteína)/químicaRESUMEN
A convenient one-pot synthesis of 2-aroylindoles using a domino palladium-catalyzed C,N-coupling/carbonylation/C,C-coupling sequence is described. The reaction involved easily prepared 2-gem-dibromovinylanilines and boronic acids under carbon monoxide. Optimized reaction conditions allowed the construction of a wide variety of highly functionalized 2-aroyl-/heteroaroylindoles in satisfactory yields.
Asunto(s)
Carbono/química , Indoles/química , Indoles/síntesis química , Nitrógeno/química , Paladio/química , Compuestos de Anilina/química , Ácidos Borónicos/química , Monóxido de Carbono/química , CatálisisRESUMEN
A series of novel combretastatin A4 analogues, in which the cis-olefinic bridge is replaced by a cyclopropyl-vinyl or a cyclopropyl-amide moiety, were synthesized and evaluated for inhibition of tubulin polymerization and antiproliferative activity. The derivative 9a with a (cis,E)-cyclopropyl-vinyl unit is the most promising compound. As expected, molecular docking of 9a has shown that only one of the cis-cyclopropyl enantiomers is a good ligand for tubulin.
Asunto(s)
Amidas/síntesis química , Ciclopropanos/síntesis química , Estilbenos/síntesis química , Compuestos de Vinilo/síntesis química , Amidas/farmacología , Sitios de Unión/efectos de los fármacos , Línea Celular Tumoral , Ciclopropanos/farmacología , Evaluación Preclínica de Medicamentos/métodos , Humanos , Unión Proteica/efectos de los fármacos , Estilbenos/farmacología , Tubulina (Proteína)/metabolismo , Compuestos de Vinilo/farmacologíaRESUMEN
An efficient synthetic route toward the synthesis of highly substituted arylethylidene-isoquinolinones/isochromanones is reported. The tandem carbopalladation/Suzuki-Miyaura coupling sequence stereoselectively provided various functionalized polycyclic compounds in moderate to excellent yields.
Asunto(s)
Alquenos/química , Cromonas/síntesis química , Isoquinolinas/síntesis química , Cromonas/química , Isoquinolinas/química , Estructura Molecular , EstereoisomerismoRESUMEN
Combretastatin A4 phosphate (CA4P) causes rapid disruption of the tumor vasculature and is currently being evaluated for antivascular therapy. We describe the initial results obtained with a noninvasive multiparametric magnetic resonance imaging (MRI) approach to assess the early effects of CA4P on rat bladder tumors implanted on nude mice. MRI (4.7 T) comprised a fast spin-echo sequence for growth curve assessment; a multislice multiecho sequence for T2 measurement before, 15 minutes after, and 24 hours after CA4P (100 mg/kg); and a fast T2w* gradient-echo sequence to assess MR signal modification under carbogen breathing before, 35 minutes after, and 24 hours after CA4P. The tumor fraction with increased T2w* signal intensity under carbogen (T+) was used to quantify CA4P effect on functional vasculature. CA4P slowed tumor growth over 24 hours and accelerated necrosis development. T+ decrease was observed already at 35 minutes post-CA4P. Early T2 increase was observed in regions becoming necrotic at 24 hours post-CA4P, as confirmed by high T2 and histology. These regions exhibited, under carbogen, a switch from T2w* signal increase before CA4P to a decrease postCA4P. The combination of carbogen-based functional MRI and T2 measurement may be useful for the early follow-up of antivascular therapy without the administration of contrast agents.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Dióxido de Carbono/farmacología , Imagen por Resonancia Magnética/instrumentación , Imagen por Resonancia Magnética/métodos , Oxígeno/farmacología , Fármacos Sensibilizantes a Radiaciones/farmacología , Estilbenos/farmacología , Neoplasias de la Vejiga Urinaria/patología , Animales , Medios de Contraste/farmacología , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neovascularización Patológica , Ratas , Factores de Tiempo , Neoplasias de la Vejiga Urinaria/metabolismoRESUMEN
Novel combretastatin analogues bearing various five-membered heterocycles with consecutive oxygen and nitrogen atoms, in place of the olefinic bridge of CA4, have been synthesized (isoxazole, isoxazoline, oxadiazole, etc). These compounds have been evaluated for cytotoxicity and their ability to inhibit the tubulin assembly. On the basis of the relative position of the aromatic A- and B-rings on the heterocyclic moiety, they could be split in two classes, the alpha,gamma- or alpha,beta-diaryl heterocyclic derivatives. In the first series, the 3,5-diaryloxadiazole 9a displayed comparable antitubulin activity to that of CA4, but was devoid of cytotoxic effects. Among the alpha,beta-diaryl heterocyclic derivatives, the 4,5-diarylisoxazole 35 exhibited greater antitubulin activity than that of CA4 (0.75 vs 1.2 microM), but modest antiproliferative activity. These data showed that minor alteration in the chemical structure of the heterocyclic ring and its relative orientation with regard to the two phenyl rings of CA4 could dramatically influence the tubulin binding properties.
Asunto(s)
Isoxazoles/síntesis química , Isoxazoles/farmacología , Estilbenos/síntesis química , Estilbenos/farmacología , Encéfalo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Humanos , Isoxazoles/química , Estructura Molecular , Unión Proteica , Estereoisomerismo , Estilbenos/química , Relación Estructura-Actividad , Tubulina (Proteína)/efectos de los fármacos , Tubulina (Proteína)/metabolismoRESUMEN
Stereospecific syntheses of the Z-E and E-Z vinylogues of combretastatin A-4, and two B-ring related analogues, were achieved through a Suzuki-Miyaura coupling. As compared to CA4, the derivative with a phenyl moiety has shown increased potency in its ability to inhibit tubulin polymerisation.