RESUMEN
Src is a nonreceptor tyrosine kinase involved in signaling pathways that control proliferation, migration, and angiogenesis. Increased Src expression and activity are associated with an increase in tumor malignancy and poor prognosis. Several quinolines and quinazolines were identified as potent and selective inhibitors of Src kinase activity.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Quinazolinas/síntesis química , Quinolinas/síntesis química , Familia-src Quinasas/antagonistas & inhibidores , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática , Humanos , Estructura Molecular , Quinazolinas/química , Quinazolinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Relación Estructura-ActividadRESUMEN
The synthesis and SAR of a series of 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor (EGF-R) kinase are described. Condensation of 3, 4-dialkoxyanilines with ethyl (ethoxymethylene)cyanoacetate followed by thermal cyclization gave, regiospecifically, 6,7-dialkoxy-4-oxo-1, 4-dihydroquinoline-3-carbonitriles. Chlorination (POCl(3)) followed by the reaction with substituted anilines furnished the 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of EGF-R kinase. An alternate synthesis of these compounds starts with a methyl 3, 4-dialkoxybenzoate. Nitration followed by reduction (Fe, NH(4)Cl, MeOH-H(2)O) gave a methyl 2-amino-4,5-dialkoxybenzoate. Amidine formation using DMF-acetal followed by cyclization using LiCH(2)CN furnished a 6,7-dialkoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile, which was transformed as before. Compounds containing acid, ester, amide, carbinol, and aldehyde groups at the 3-position of the quinoline ring were also prepared for comparison, as were several 1-anilino-6,7-dimethoxyisoquinoline-4-carbonitriles. The compounds were evaluated for their ability to inhibit the autophosphorylation of the catalytic domain of EGF-R. The SAR of these inhibitors with respect to the nature of the 6,7-alkoxy groups, the aniline substituents, and the substituent at the 3-position was studied. The compounds were further evaluated for their ability to inhibit the growth of cell lines that overexpress EGF-R or HER-2. It was found that 4-anilinoquinoline-3-carbonitriles are effective inhibitors of EGF-R kinase with activity comparable to the 4-anilinoquinazoline-based inhibitors. A new homology model of EGF-R kinase was constructed based on the X-ray structures of Hck and FGF receptor-1 kinase. The model suggests that with the quinazoline-based inhibitors, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 830. It is proposed that the quinoline-3-carbonitriles bind in a similar manner where the water molecule is displaced by the cyano group which interacts with the same Thr residue.
Asunto(s)
Compuestos de Anilina/síntesis química , Antineoplásicos/síntesis química , Inhibidores Enzimáticos/síntesis química , Receptores ErbB/antagonistas & inhibidores , Nitrilos/síntesis química , Quinazolinas/síntesis química , Quinolinas/síntesis química , Compuestos de Anilina/química , Compuestos de Anilina/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Fluorometría , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Nitrilos/química , Nitrilos/farmacología , Fosforilación , Quinazolinas/química , Quinazolinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A series of 3-cyano-4-(phenoxyanilino)cyanoquinolines has been prepared as MEK (MAP kinase kinase) inhibitors. The best activity is seen with alkoxy groups at both the 6- and 7-positions. The lead compounds show low nanomolar IC50's against MAP kinase kinase, and have potent inhibitory activity in tumor cells.
Asunto(s)
Antineoplásicos/síntesis química , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Nitrilos/farmacología , Quinolinas/farmacología , Compuestos de Anilina/síntesis química , Compuestos de Anilina/farmacología , Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Neoplasias del Colon/patología , Ensayo de Inmunoadsorción Enzimática , Humanos , Concentración 50 Inhibidora , Nitrilos/síntesis química , Quinolinas/síntesis química , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
It has been shown previously that 4-anilino quinazolines compete with the ability of ATP to bind the epidermal growth factor receptor (EGF-R), inhibit EGF-stimulated autophosphorylation of tyrosine residues in EGF-R, and block EGF-mediated growth. Since millimolar concentrations of ATP in cells could reduce the efficacy of 4-anilino quinazolines in cells and the activity of these compounds would not be sustained once they were removed from the body, we reasoned that irreversible inhibitors of EGF-R might improve the activity of this series of compounds in animals. Molecular modeling of the EGF-R kinase domain was used to design irreversible inhibitors. We herein describe one such inhibitor: N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]2-butynamide, known as CL-387,785. This compound covalently bound to EGF-R. It also specifically inhibited kinase activity of the protein (IC50 = 370+/-120 pM), blocked EGF-stimulated autophosphorylation of the receptor in cells (ic50 approximately 5 nM), inhibited cell proliferation (IC50 = 31-125 nM) primarily in a cytostatic manner in cell lines that overexpress EGF-R or c-erbB-2, and profoundly blocked the growth of a tumor that overexpresses EGF-R in nude mice (when given orally at 80 mg/kg/day for 10 days, daily). We conclude that CL-387,785 is useful for studying the interaction of small molecules with EGF-R and may have clinical utility.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Receptores ErbB/antagonistas & inhibidores , Quinazolinas/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/metabolismo , Receptores ErbB/metabolismo , Femenino , Ratones , Ratones Desnudos , Modelos Moleculares , Trasplante de Neoplasias , Neoplasias Experimentales/tratamiento farmacológico , Fosforilación/efectos de los fármacos , Quinazolinas/síntesis química , Células Tumorales CultivadasAsunto(s)
Antihipertensivos/síntesis química , Dinoprostona/análogos & derivados , Prostaglandinas E Sintéticas/farmacología , Administración Oral , Administración Tópica , Animales , Presión Sanguínea/efectos de los fármacos , Prostaglandinas E Sintéticas/administración & dosificación , Ratas , Factores de TiempoRESUMEN
The interesting bronchodilator activity of l-11-deoxy-11 alpha-[(2-hydroxyethyl)thio]prostaglandin E2 methyl ester (3a) is described. The preparation of 3a and its analogues by Michael-type additions to various members of the PGA series or by total synthesis using the lithiocuprate conjugate addition process is also described. Structure-activity relationships in this series are discussed.
Asunto(s)
Broncodilatadores/síntesis química , Prostaglandinas E Sintéticas/síntesis química , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Perros , Cobayas , Hemodinámica/efectos de los fármacos , Métodos , Prostaglandinas E Sintéticas/farmacología , EstereoisomerismoRESUMEN
Prostaglandin congeners wherein the 15-hydroxy group is moved to the C16, C17, or C20 position or is replaced by a hydroxymethyl group were prepared via the 1, 4-addition of a lithium trialkyl-trans-alkenyl alanate to an appropriate cyclopentenone. Several of the 16-hydroxy derivatives showed significant activity as constrictors of the isolated gerbil colon and in bronchodilator and anti-secretory assays.