RESUMEN
Novel azole compounds were prepared which demonstrated potent hCB2 binding activities with antioxidant activity for a selected compound. These compounds show good selectivity over the hCB1 receptor and are full agonists at the hCB2 receptor.
Asunto(s)
Azoles/química , Azoles/metabolismo , Agonistas de Receptores de Cannabinoides/química , Agonistas de Receptores de Cannabinoides/metabolismo , Receptor Cannabinoide CB2/agonistas , Receptor Cannabinoide CB2/metabolismo , Animales , Células CHO , Cannabinoides/química , Cannabinoides/metabolismo , Cricetinae , Cricetulus , HumanosRESUMEN
CDC25 phosphatases are key actors in cyclin-dependent kinases activation whose role is essential at various stages of the cell cycle. CDC25 expression is upregulated in a number of human cancers. CDC25 phosphatases are therefore thought to represent promising novel targets in cancer therapy. Here, we report the identification and the characterization of IRC-083864, an original bis-quinone moiety that is a potent and selective inhibitor of CDC25 phosphatases in the low nanomolar range. IRC-083864 inhibits cell proliferation of a number of cell lines, regardless of their resistance to other drugs. It irreversibly inhibits cell proliferation and cell cycle progression and prevents entry into mitosis. In addition, it inhibits the growth of HCT-116 tumor spheroids with induction of p21 and apoptosis. Finally, IRC-083864 reduced tumor growth in mice with established human prostatic and pancreatic tumor xenografts. This study describes a novel compound, which merits further study as a potential anticancer agent.
Asunto(s)
Benzotiazoles/uso terapéutico , Benzoxazoles/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Quinonas/uso terapéutico , Fosfatasas cdc25/antagonistas & inhibidores , Animales , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Línea Celular Tumoral/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/enzimología , Neoplasias del Colon/patología , Quinasas Ciclina-Dependientes/metabolismo , Citometría de Flujo , Humanos , Ratones , Ratones Desnudos , Trasplante HeterólogoRESUMEN
Tubulin is a validated target for antitumor drugs. However, the effectiveness of these microtubule-interacting agents is limited by the fact that they are substrates for drug efflux pumps (P-glycoprotein) and/or by the acquisition of point mutations in tubulin residues important for drug-tubulin binding. To bypass these resistance systems, we have identified and characterized a novel synthetic imidazole derivative IRC-083927, which inhibits the tubulin polymerization by a binding to the colchicine site. IRC-083927 inhibits in vitro cell growth of human cancer cell lines in the low nanomolar range. More interesting, it remains highly active against cell lines resistant to microtubule-interacting agents (taxanes, Vinca alkaloids, or epothilones). Such resistances are due to the presence of efflux pumps (NCI-H69/LX4 resistant to navelbine and paclitaxel) and/or the presence of mutations on beta-tubulin and on alpha-tubulin and beta-tubulin (A549.EpoB40/A549.EpoB480 resistant to epothilone B or paclitaxel). IRC-083927 displayed cell cycle arrest in G(2)-M phase in tumor cells, including in the drug-resistant cells. In addition, IRC-083927 inhibited endothelial cell proliferation in vitro and vessel formation in the low nanomolar range supporting an antiangiogenic behavior. Finally, chronic oral treatment with IRC-083927 (5 mg/kg) inhibits the growth of two human tumor xenografts in nude mice (C33-A, human cervical cancer and MDA-MB-231, human hormone-independent breast cancer). Together, the antitumor effects induced by IRC-083927 on tumor models resistant to tubulin agents support further investigations to fully evaluate its potential for the treatment of advanced cancers, particularly those resistant to current clinically available drugs.
Asunto(s)
Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Imidazoles/farmacología , Sulfonamidas/farmacología , Tubulina (Proteína)/metabolismo , Animales , Antineoplásicos/farmacocinética , Disponibilidad Biológica , Ciclo Celular/efectos de los fármacos , Resistencia a Antineoplásicos , Humanos , Ratones , Neovascularización Patológica , Trasplante HeterólogoRESUMEN
A series of 22-hydroxyacuminatine analogs was prepared by using different Friedländer condensations. Several of the new compounds were tested for antiproliferative activity on cancer cell lines and for topoisomerase I inhibitory activity.
Asunto(s)
Antineoplásicos/farmacología , Indolizinas/síntesis química , Neoplasias/tratamiento farmacológico , Quinolinas/síntesis química , Antineoplásicos/síntesis química , ADN-Topoisomerasas de Tipo I/genética , Humanos , Indolizinas/química , Indolizinas/farmacología , Estructura Molecular , Neoplasias/enzimología , Quinolinas/química , Quinolinas/farmacología , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I , Células Tumorales CultivadasRESUMEN
The CDC25 phosphatases are key regulators of cell cycle progression and play a central role in the checkpoint response to DNA damage. Their inhibition may therefore represent a promising therapeutic approach in oncology, and small molecule design strategies are currently leading to the identification of various classes of CDC25 inhibitors. Most structures developed so far are quinonoid-based compounds, but also phosphate surrogates or electrophilic entities. Considering the characteristics of the highly conserved active sites of the enzymes, many mechanisms of action have been proposed for these inhibitors. Quinonoid compounds may oxidize the catalytic site cysteine, but can also be considered as Michaël acceptors capable of reacting with the activated thiolate or other electrophilic entities. Phosphate surrogates are thought to interfere with the arginine residue, leading to reversible enzyme inhibition. But some inhibitors can combine in the same molecule several of these mechanisms, thus by fitting into the active site of the enzyme through one part of the molecule and bringing the reactive moiety in close proximity to the catalytic cysteine. This review summarizes novel classes of inhibitors that show specificity for the CDC25s over other phosphatases, cause cell proliferation inhibition and cell cycle arrest in vitro but also, for several of them, inhibition of xenografted tumoral cell growth in vivo. These promising results confirm the interest of the inhibition of CDC25 phosphatases as an anticancer therapeutic strategy.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Fosfatasas cdc25/antagonistas & inhibidores , Animales , Inhibidores Enzimáticos/química , HumanosRESUMEN
A series of 4-arylimidazole carbamates was synthesized and their binding affinities to the site-2 sodium (Na+) channel were determined. SAR studies led to the identification of compound 10, a potent Na+ channel blocker which was efficacious in pain models in vivo.
Asunto(s)
Carbamatos/síntesis química , Carbamatos/farmacología , Imidazoles/síntesis química , Imidazoles/farmacología , Dolor/tratamiento farmacológico , Dolor/etiología , Enfermedades del Sistema Nervioso Periférico/complicaciones , Bloqueadores de los Canales de Sodio/síntesis química , Bloqueadores de los Canales de Sodio/farmacología , Animales , Batracotoxinas , Unión Competitiva/efectos de los fármacos , Carragenina , Humanos , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Indicadores y Reactivos , Microsomas/efectos de los fármacos , Microsomas/metabolismo , Ratas , Sodio/metabolismo , Relación Estructura-Actividad , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Veratridina/farmacologíaRESUMEN
A series of dipeptides with dual inhibitory activities on calpain and lipid peroxidation were prepared to target the intracellular calpain. This optimization program focused on the variations of the linker and the N-terminal amino acid of the peptidic core. Two compounds 6d-05 and 6d-08 exhibited potent intracellular calpain inhibition. The polar surface area and the number of rotors appeared to be critical descriptors to account for the behavior of these hybrid molecules in the cellular calpain assay.
Asunto(s)
Antioxidantes/farmacología , Calpaína/antagonistas & inhibidores , Muerte Celular/efectos de los fármacos , Dipéptidos/farmacología , Peroxidación de Lípido/efectos de los fármacos , Animales , Antioxidantes/síntesis química , Encéfalo/efectos de los fármacos , Calpaína/metabolismo , Dipéptidos/síntesis química , Glioma/tratamiento farmacológico , Humanos , Concentración 50 Inhibidora , Microsomas/efectos de los fármacos , Ratas , Relación Estructura-ActividadRESUMEN
BN80927 belongs to a novel family of camptothecin analogs, the homocamptothecins, developed on the concept of topoisomerase I (Topo I) inhibition and characterized by a stable seven-membered beta-hydroxylactone ring. Preclinical data reported here show that BN80927 retains Topo I poisoning activity in cell-free assay (DNA relaxation) as well as in living cells, in which in vivo complexes of topoisomerase experiments and quantification of DNA-protein-complexes stabilization, have confirmed the higher potency of BN80927 as compared with the Topo I inhibitor SN38. In addition, BN80927 inhibits Topo II-mediated DNA relaxation in vitro but without cleavable-complex stabilization, thus indicating catalytic inhibition. Moreover, a Topo I-altered cell line (KBSTP2), resistant to SN38, remains sensitive to BN80927, suggesting that a part of the antiproliferative effects of BN80927 are mediated by a Topo I-independent pathway. This hypothesis is also supported by in vitro data showing an antiproliferative activity of BN80927 on a model of resistance related to the noncycling state of cells (G(0)-G(1) synchronized). In cell growth assays, BN80927 is a very potent antiproliferative agent as shown by IC(50) values consistently lower than those of SN38 in tumor cell lines as well as in their related drug-resistant lines. BN80927 shows high efficiency in vivo in tumor xenograft studies using human androgen-independent prostate tumors PC3 and DU145. Altogether, these data strongly support the clinical development of BN80927.
Asunto(s)
Antineoplásicos/farmacología , Camptotecina/análogos & derivados , Camptotecina/farmacología , Neoplasias de la Próstata/tratamiento farmacológico , Adenocarcinoma/sangre , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/enzimología , Adenocarcinoma/patología , Animales , Camptotecina/sangre , División Celular/efectos de los fármacos , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo I/metabolismo , ADN-Topoisomerasas de Tipo II/metabolismo , ADN Superhelicoidal/efectos de los fármacos , ADN Superhelicoidal/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Inhibidores Enzimáticos/farmacología , Células HL-60 , Humanos , Células K562 , Masculino , Ratones , Ratones Desnudos , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias Hormono-Dependientes/patología , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/enzimología , Neoplasias de la Próstata/patología , Inhibidores de Topoisomerasa I , Inhibidores de Topoisomerasa II , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A series of molecules with dual inhibitory activities on calpain and lipid peroxidation were synthesized. These hybrid compounds were built on the calpain pharmacophore 2-hydroxytetrahydrofuran linked to a set of antioxidants via a l-leucine linker. Compound 7, the most potent in cellular calpain and lipid peroxidation inhibitions, provided effective protection against glial cell death induced by maitotoxin.
Asunto(s)
Antioxidantes/síntesis química , Calpaína/antagonistas & inhibidores , Muerte Celular/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Inhibidores de la Lipooxigenasa/síntesis química , Antioxidantes/farmacología , Calpaína/metabolismo , Furanos/química , Humanos , Concentración 50 Inhibidora , Leucina/química , Inhibidores de la Lipooxigenasa/farmacología , Neuroglía , Relación Estructura-ActividadRESUMEN
A series of 2-alkyl-4-arylimidazoles were prepared and their binding affinities to the site-2 sodium (Na+) channel were determined. SAR studies led to highly potent Na+ channel blockers.
Asunto(s)
Bloqueadores de los Canales de Sodio/síntesis química , Canales de Sodio/metabolismo , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacología , Sitios de Unión , Encéfalo/metabolismo , Carbolinas/química , Células Cultivadas , Electrofisiología , Concentración 50 Inhibidora , Ratas , Bloqueadores de los Canales de Sodio/farmacología , Relación Estructura-Actividad , Veratridina/farmacologíaRESUMEN
Novel phenolic thiazoles compounds were prepared which demonstrated potent antioxidant activity and potent in vivo neuroprotection in mitochondrial toxin models and also possess good oral bioavailability.
Asunto(s)
Antioxidantes/administración & dosificación , Fármacos Neuroprotectores/administración & dosificación , Fenoles/administración & dosificación , Tiazoles/administración & dosificación , Administración Oral , Animales , Antioxidantes/química , Relación Dosis-Respuesta a Droga , Intoxicación por MPTP/metabolismo , Intoxicación por MPTP/prevención & control , Ratones , Fármacos Neuroprotectores/química , Fenoles/química , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Tiazoles/químicaRESUMEN
A series of hybrid compounds possessing an nNOS pharmacophore linked to an antioxidant fragment has been synthesized. Among them, compound 8d, a propofol derivative, displayed the greatest dual potencies against nNOS (IC(50)=0.12 microM) and lipid peroxidation (IC(50)=0.4 microM) accompanied with e/nNOS selectivity (67.5). This shows that nNOS was able to accommodate very bulky groups such as di-tert-butyl or di-iso-propyl phenol in its active site.
Asunto(s)
Antioxidantes/síntesis química , Antioxidantes/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Peroxidación de Lípido/efectos de los fármacos , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/farmacología , Óxido Nítrico Sintasa de Tipo I , Óxido Nítrico Sintasa de Tipo III , Propofol/análogos & derivados , Propofol/síntesis química , Propofol/farmacología , Especificidad por SustratoRESUMEN
The synthesis and biological activity of novel lipoic acid analogues are reported. Lipoic acid and structural homologues coupled to arylthiophene amidine via carboxamide linkers are metabolic antioxidants capable of protecting neuronal cells against glutamate cytotoxicity, preventing loss of intracellular glutathione, and inhibit nitric oxide synthase.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ácido Tióctico/análogos & derivados , Animales , Antioxidantes/síntesis química , Antioxidantes/farmacología , Arginina/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citrulina/metabolismo , Diseño de Fármacos , Ácido Glutámico/metabolismo , Ácido Glutámico/toxicidad , Glutatión/deficiencia , Glutatión/metabolismo , Ratones , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacología , Óxido Nítrico Sintasa/toxicidad , Óxido Nítrico Sintasa de Tipo I , Estrés Oxidativo/efectos de los fármacos , Ácido Tióctico/síntesis química , Ácido Tióctico/farmacologíaRESUMEN
Vinblastine and vinorelbine analogues have been synthesised by reacting new versatile electrophilic vindoline derivatives with various 3-substituted indoles. The resulting compounds have been evaluated for their antimitotic properties, but exhibited less potent activities in comparison with the standard binary Vinca alkaloids.