RESUMEN
Here we describe the discovery and optimization of hexahydro-2H-pyrano[3,2-c]quinolines (HHPQs) as potent and selective inhibitors of the mitotic kinesin-5 originally found during a high-throughput screening (HTS) campaign sampling our in-house compound collection. The compounds optimized subsequently and characterized herein were potently inhibiting the ATPase activity of Kinesin-5 and also exhibited consistent cellular activity, in that cells arrested in mitosis and apoptosis induction could be observed. X-ray crystallographic data demonstrated that these inhibitors bind in an allosteric pocket of Kinesin-5 distant from the nucleotide and microtubule binding sites. The selected clinical candidate EMD 534085 caused strong growth inhibition in human tumor xenograft models using Colo 205 colon carcinoma cells at doses below 30mg/kg administered twice weekly without showing severe toxicity as determined by loss of body weight.
Asunto(s)
Antineoplásicos/química , Inhibidores Enzimáticos/química , Cinesinas/antagonistas & inhibidores , Mitosis , Quinolinas/química , Regulación Alostérica , Animales , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Sitios de Unión , Línea Celular Tumoral , Cristalografía por Rayos X , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Ensayos Analíticos de Alto Rendimiento , Humanos , Cinesinas/metabolismo , Ratones , Quinolinas/síntesis química , Quinolinas/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
A highly convergent total synthesis of the potent anticancer agent (+)-phorboxazole A (1) is accomplished. Four components (3-6) are assembled with considerations for control of absolute and relative stereochemistry. Iterative asymmetric allylation methodology addresses key stereochemical features in the preparation of the 2,6-cis- and 2,6-trans-tetrahydropyranyl rings of the C3-C19 component (3). The stereocontrolled asymmetric allylation process is also used for development of the C28-C41 fragment (4). Novel Barbier coupling reactions of alpha-iodomethyl oxazoles and related thiazoles are described with samarium iodide. The convergent assembly of components 4 and 5 features formation of the fully substituted C22-C26 pyran by intramolecular capture of an allyl cation intermediate with high facial selectivity, and further efforts lead to E-C19/C20 olefination. The synthesis culminates with use of a modified Julia olefination for attachment of the C42-C46 segment and subsequent late-stage macrocyclization by installation of the (Z)-C2/C3 alpha,beta-unsaturated lactone.
