RESUMEN
Tankyrases (TNKS/TNKS2) belong to the poly(ADP-ribose) polymerase family. Inhibition of their enzymatic activities attenuates the Wnt/ß-catenin signaling, which plays an important role in cancer pathogenesis. We previously reported the discovery of RK-287107, a spiroindoline-based, highly selective, potent tankyrase inhibitor. Herein we describe the optimization process of RK-287107 leading to RK-582, which exhibits a markedly improved robust tumor growth inhibition in a COLO-320DM mouse xenograft model when orally administered. In addition to the dose-dependent elevation and attenuation of the levels of biomarkers AXIN2 and ß-catenin, respectively, results of the TCF reporter and cell proliferation studies on COLO-320DM are discussed.
Asunto(s)
Neoplasias del Colon/tratamiento farmacológico , Diseño de Fármacos , Descubrimiento de Drogas/métodos , Inhibidores Enzimáticos/administración & dosificación , Tanquirasas/antagonistas & inhibidores , Administración Oral , Animales , Línea Celular Tumoral , Neoplasias del Colon/enzimología , Inhibidores Enzimáticos/química , Femenino , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Estructura Terciaria de Proteína , Ratas , Tanquirasas/química , Tanquirasas/metabolismo , Resultado del Tratamiento , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
The canonical WNT pathway plays an important role in cancer pathogenesis. Inhibition of poly(ADP-ribose) polymerase catalytic activity of the tankyrases (TNKS/TNKS2) has been reported to reduce the Wnt/ß-catenin signal by preventing poly ADP-ribosylation-dependent degradation of AXIN, a negative regulator of Wnt/ß-catenin signaling. With the goal of investigating the effects of tankyrase and Wnt pathway inhibition on tumor growth, we set out to find small-molecule inhibitors of TNKS/TNKS2 with suitable drug-like properties. Starting from 1a, a high-throughput screening hit, the spiroindoline derivative 40c (RK-287107) was discovered as a potent TNKS/TNKS2 inhibitor with >7000-fold selectivity against the PARP1 enzyme, which inhibits WNT-responsive TCF reporter activity and proliferation of human colorectal cancer cell line COLO-320DM. RK-287107 also demonstrated dose-dependent tumor growth inhibition in a mouse xenograft model. These observations suggest that RK-287107 is a promising lead compound for the development of novel tankyrase inhibitors as anticancer agents.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Indoles/química , Indoles/farmacología , Compuestos de Espiro/farmacología , Tanquirasas/antagonistas & inhibidores , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología , Compuestos de Espiro/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The synthesis and antibacterial activity of (7S)-7-sulfur-azetidin-3-yl lincomycin derivatives are described. Modification was achieved by a simple reaction of (7R)-7-O-methanesulfonyllincomycin and the corresponding substituted azetidine-2-thiol. Several compounds first showed moderate antibacterial activity against Streptococcus pneumoniae and Streptococcus pyogenes with erm gene as lincomycin derivatives.
Asunto(s)
Antibacterianos/farmacología , Azetidinas/farmacología , Lincomicina/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Azetidinas/síntesis química , Azetidinas/química , Genes Bacterianos , Lincomicina/síntesis química , Lincomicina/química , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/genética , Streptococcus pyogenes/efectos de los fármacos , Streptococcus pyogenes/genética , Relación Estructura-ActividadRESUMEN
The design and synthesis of 16-membered azalides modified at the C-15 and 4'' positions are described. The compounds we report here are characterized by an arylpropenyl group attached to the C-15 position of macrolactone and a carbamoyl group at the C-4'' position in a neutral sugar. Introduction of alkylcarbamoyl groups to the C-4'' position was regioselectively achieved by unique and convenient methods via acyl migration. As a result of optimization at the C-3 and 15 positions, several compounds were found to have potent activity against mef- and erm-resistant bacterial strains. These results suggest that 16-membered azalides could be promising compounds as clinical candidates.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Compuestos Aza/síntesis química , Compuestos Aza/farmacología , Macrólidos/síntesis química , Macrólidos/farmacología , Proteínas Bacterianas/genética , Farmacorresistencia Bacteriana/genética , Bacterias Grampositivas/efectos de los fármacos , Indicadores y Reactivos , Proteínas de la Membrana/genética , Pruebas de Sensibilidad Microbiana , Streptococcus pneumoniae/efectos de los fármacosRESUMEN
A new series of 1beta-methyl carbapenems possessing a 6,7-disubstituted imidazo[5,1-b]thiazol-2-yl group directly attached to the C-2 position of the carbapenem nucleus was prepared, and their activities against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. First, a benzyl moiety was introduced at the C-6 position of imidazo[5,1-b]thiazole attached to the carbapenem. These benzylated molecules showed potent anti-MRSA activity, but poor water solubility. In order to overcome this drawback, we designed and synthesized di- and tricationic carbapenems and finally discovered a novel carbapenem (15i), which exhibited excellent anti-MRSA activity and good water solubility.
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Carbapenémicos/síntesis química , Carbapenémicos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Antibacterianos/química , Carbapenémicos/química , Cationes , Pruebas de Sensibilidad Microbiana , SolubilidadRESUMEN
A new series of 1beta-methyl carbapenems possessing a 6,7-disubstituted imidazo[5,1-b]thiazol-2-yl group directly attached to the C-2 position of the carbapenem nucleus was prepared, and the activities of these compounds against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. To study the effect of basic moieties on anti-MRSA activity, we introduced an amino, or imino, or amidino group at the 6-position of imidazo[5,1-b]thiazole in place of the carbamoylmethyl moiety of CP5068. Anti-MRSA activities of almost all basic group-substituted carbapenems were improved, though some of the compounds showed stronger acute toxicity in mice than IPM. In order to decrease the toxicity without decreasing the activity, we introduced various additional functionalities around the basic moiety. Finally, we obtained CP5484, which has excellent anti-MRSA activity and low acute toxicity.
Asunto(s)
Antibacterianos/farmacología , Carbapenémicos/farmacología , Resistencia a la Meticilina , Staphylococcus aureus/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/toxicidad , Carbapenémicos/síntesis química , Carbapenémicos/toxicidad , Imidazoles/química , Cinética , Pruebas de Sensibilidad Microbiana , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
A new series of 1beta-methyl carbapenems, possessing a 7-substituted imidazo[5,1-b]thiazol-2-yl group directly attached to the C-2 position of the carbapenem nucleus, was synthesized and evaluated for antibacterial activity. These compounds showed potent activities against Gram-positive bacteria, in particular methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae (PRSP). They also exhibited potent activity against beta-lactamase-negative ampicillin-resistant Haemophilus influenzae (BLNAR).
Asunto(s)
Antibacterianos/síntesis química , Antibacterianos/farmacología , Carbapenémicos/síntesis química , Carbapenémicos/farmacología , Haemophilus influenzae/efectos de los fármacos , Compuestos de Piridinio/síntesis química , Compuestos de Piridinio/farmacología , Staphylococcus aureus/efectos de los fármacos , Streptococcus pneumoniae/efectos de los fármacos , Antibacterianos/química , Carbapenémicos/química , Pruebas de Sensibilidad Microbiana , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The efficacy of ME1036, a novel parenteral carbapenem, was compared with that of vancomycin by using a rabbit model of methicillin-resistant Staphylococcus aureus (MRSA) endocarditis. Compared with vancomycin, ME1036 reduced the bacterial counts in the vegetations at a lower dosage or over a shorter period of administration when it was used for the treatment of MRSA endocarditis.
Asunto(s)
Antibacterianos/uso terapéutico , Carbapenémicos/uso terapéutico , Endocarditis Bacteriana/tratamiento farmacológico , Resistencia a la Meticilina , Infecciones Estafilocócicas/tratamiento farmacológico , Staphylococcus aureus/efectos de los fármacos , Animales , Antibacterianos/farmacocinética , Carbapenémicos/farmacocinética , Recuento de Colonia Microbiana , Modelos Animales de Enfermedad , Endocarditis Bacteriana/microbiología , Femenino , Humanos , Pruebas de Sensibilidad Microbiana , Conejos , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus/aislamiento & purificación , Resultado del Tratamiento , Vancomicina/farmacocinética , Vancomicina/uso terapéuticoRESUMEN
ME1036, formerly CP5609, is a novel parenteral carbapenem with a 7-acylated imidazo[5,1-b]thiazole-2-yl group directly attached to the carbapenem moiety of the C-2 position. The present study evaluated the in vitro activities of ME1036 against clinical isolates of gram-positive and gram-negative bacteria. ME1036 displayed broad activity against aerobic gram-positive and gram-negative bacteria. Unlike other marketed beta-lactam antibiotics, ME1036 maintained excellent activity against multiple-drug-resistant gram-positive bacteria, such as methicillin-resistant staphylococci and penicillin-resistant Streptococcus pneumoniae (PRSP). The MICs of this compound at which 90% of isolates were inhibited were 2 microg/ml for methicillin-resistant Staphylococcus aureus (MRSA), 2 microg/ml for methicillin-resistant coagulase-negative staphylococci, and 0.031 microg/ml for PRSP. In time-kill studies with six strains of MRSA, ME1036 at four times the MIC caused a time-dependent decrease in the numbers of viable MRSA cells. The activity of ME1036 against MRSA is related to its high affinity for penicillin-binding protein 2a, for which the 50% inhibitory concentration of ME1036 was approximately 300-fold lower than that of imipenem. In conclusion, ME1036 demonstrated a broad antibacterial spectrum and high levels of activity in vitro against staphylococci, including beta-lactam-resistant strains.