RESUMEN
Structure-activity studies of 4-substituted-2,5-dimethoxyphenethylamines led to the discovery of 2,5-dimethoxy-4-thiotrifluoromethylphenethylamines, including CYB210010, a potent and long-acting serotonin 5-HT2 receptor agonist. CYB210010 exhibited high agonist potency at 5-HT2A and 5-HT2C receptors, modest selectivity over 5-HT2B, 5-HT1A, 5-HT6, and adrenergic α2A receptors, and lacked activity at monoamine transporters and over 70 other proteins. CYB210010 (0.1-3 mg/kg) elicited a head-twitch response (HTR) and could be administered subchronically at threshold doses without behavioral tolerance. CYB210010 was orally bioavailable in three species, readily and preferentially crossed into the CNS, engaged frontal cortex 5-HT2A receptors, and increased the expression of genes involved in neuroplasticity in the frontal cortex. CYB210010 represents a new tool molecule for investigating the therapeutic potential of 5-HT2 receptor activation. In addition, several other compounds with high 5-HT2A receptor potency, yet with little or no HTR activity, were discovered, providing the groundwork for the development of nonpsychedelic 5-HT2A receptor ligands.
Asunto(s)
Fenetilaminas , Agonistas del Receptor de Serotonina 5-HT2 , Relación Estructura-Actividad , Animales , Humanos , Fenetilaminas/farmacología , Fenetilaminas/química , Fenetilaminas/síntesis química , Administración Oral , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Agonistas del Receptor de Serotonina 5-HT2/química , Agonistas del Receptor de Serotonina 5-HT2/síntesis química , Masculino , Disponibilidad Biológica , Ratas , Ratones , Ratas Sprague-Dawley , Descubrimiento de Drogas , Receptores de Serotonina 5-HT2/metabolismo , Receptor de Serotonina 5-HT2A/metabolismoRESUMEN
Macrocyclic pyrrolobenzodiazepine dimers were designed and evaluated for use as antibody-drug conjugate payloads. Initial structure-activity exploration established that macrocyclization could increase the potency of PBD dimers compared with non-macrocyclic analogs. Further optimization overcame activity-limiting solubility issues, leading to compounds with highly potent (picomolar) activity against several cancer cell lines. High levels of in vitro potency and specificity were demonstrated with an anti-mesothelin conjugate.
Asunto(s)
Anticuerpos/metabolismo , Antineoplásicos/farmacología , Benzodiazepinas/farmacología , Compuestos Macrocíclicos/farmacología , Pirroles/farmacología , Anticuerpos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Benzodiazepinas/síntesis química , Benzodiazepinas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Dimerización , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Estructura Molecular , Pirroles/síntesis química , Pirroles/química , Solubilidad , Relación Estructura-ActividadRESUMEN
Bivalent heterodimeric IAP antagonists that incorporate (R)-tetrahydroisoquinoline in the P3' subunit show high affinity for the BIR2 domain and demonstrated potent IAP inhibitory activities in biochemical and cellular assays. Potent in vivo efficacy was observed in a variety of human tumor xenograft models. The bivalent heterodimeric molecule 3 with a P3-P3' benzamide linker induced pharmacodynamic markers of apoptosis and was efficacious when administered intravenously at a dose of 1mg/kg to mice harboring A875 human melanoma tumors. Analog 5, with a polyamine group incorporated at the P2' thiovaline side chain exhibited antiproliferative activity against the P-gp expressing HCT116/VM46 cell line.
Asunto(s)
Antineoplásicos/farmacología , Descubrimiento de Drogas , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Melanoma/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Tetrahidroisoquinolinas/química , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Sitios de Unión , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Moleculares , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Traditionally, C-H oxidation reactions install oxidized functionality onto a preformed molecular skeleton, resulting in a local molecular change. The use of C-H activation chemistry to construct complex molecular scaffolds is a new area with tremendous potential in synthesis. We report a Pd(II)/bis-sulfoxide-catalyzed dehydrogenative Diels-Alder reaction that converts simple terminal olefins into complex cycloadducts in a single operation.
Asunto(s)
Alquenos/química , Cicloparafinas/síntesis química , Compuestos Heterocíclicos/síntesis química , Catálisis , Ciclización , Cicloparafinas/química , Compuestos Heterocíclicos/química , Modelos Moleculares , Estructura Molecular , Oxidación-Reducción , Paladio/química , Safrol/análogos & derivados , Safrol/química , EstereoisomerismoRESUMEN
Among the frontier challenges in chemistry in the twenty-first century are the interconnected goals of increasing synthetic efficiency and diversity in the construction of complex molecules. Oxidation reactions of C-H bonds, particularly when applied at late stages of complex molecule syntheses, hold special promise for achieving both these goals. Here we report a late-stage C-H oxidation strategy in the total synthesis of 6-deoxyerythronolide B (6-dEB), the aglycone precursor to the erythromycin antibiotics. An advanced intermediate is cyclized to give the 14-membered macrocyclic core of 6-dEB using a late-stage (step 19 of 22) C-H oxidative macrolactonization reaction that proceeds with high regio-, chemo- and diastereoselectivity (>40:1). A chelate-controlled model for macrolactonization predicted the stereochemical outcome of C-O bond formation and guided the discovery of conditions for synthesizing the first diastereomeric 13-epi-6-dEB precursor. Overall, this C-H oxidation strategy affords a highly efficient and stereochemically versatile synthesis of the erythromycin core.