RESUMEN
Treatment of the 2,3-isopropylidene acetal of the title dithioxyloside with 2,4,5-triiodoimidazole-PPh3 caused replacement of the 4-hydroxyl group by iodine to afford 82% of the 4-axial iodide 6, converted by base into 4-cyanophenyl 2,3-O-isopropylidene-1,5-dithio-beta-D-glycero-pent-3-enopyranoside++ + (8). Acid treatment of 8 gave 87% of the deacetonated glycos-3-ulose, borohydride reduction of which afforded 63% of 4-cyanophenyl 4-deoxy-1,5-dithio-alpha-L-threo-pentopyranoside (3), together with 27% of the 3-axial epimer. The 3-methyl ether of the title dithioxyloside was satisfactorily prepared via 2,4-protection as the cyclic phenylboronate, methylation, and deprotection; alternative strategy via the 2,4-bis(triisopropylsilyl) ether was complicated because of silyl-group migration under methylation conditions.
Asunto(s)
Fibrinolíticos/síntesis química , Glicósidos/química , Glicósidos/síntesis química , Cromatografía en Capa Delgada , Fibrinolíticos/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Estructura Molecular , Nitrilos , Relación Estructura-ActividadRESUMEN
2,3-Oxidosqualene lanosterol-cyclase (OSC; EC 5.4.99.7) is an attractive target for the design of compounds that block hepatic cholesterol biosynthesis. (4a alpha, 5 alpha, 6 beta, 8a beta)-Decahydro-5,8a-dimethyl-2-(1,5,9-trimethyldecyl)-6- isoquinolinol (1) and simplified analogs have been devised to inhibit this enzyme by mimicking the postulated pro-C-8 high-energy intermediary carbocation occurring during the cyclization-rearrangement pathway. In order to gain an understanding into the mechanism by which these types of molecules inhibit OSC, we have synthesized a series of substituted isoquinoline derivatives 3 and investigated the structural and stereoelectronic requirements, and their stringency, that make 3 potential high-energy intermediate analogs of OSC. Determination of the IC50 values of the different compounds with rat liver microsomal cyclase, allowed the study of the relative importance of (i) the nature and the stereochemistry of the nitrogen side chain, (ii) the presence of methyl groups at C-5 and C-8a (ring junction), (iii) the presence and stereochemistry of the C-6 hydroxyl group, (iv) the nature of the ring junction, and (v) the absolute configuration of the bicyclic system. The resulting structure-activity relationships seem to validate the mechanism of action of these inhibitors as analogs of a pro-C-8 high-energy intermediate and delineate the minimal requirements for the design of efficient isoquinoline-based, or simplified, OSC inhibitors.
Asunto(s)
Anticolesterolemiantes/química , Inhibidores Enzimáticos/química , Transferasas Intramoleculares , Isomerasas/antagonistas & inhibidores , Isoquinolinas/farmacología , Animales , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/farmacología , Colesterol/biosíntesis , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Isoquinolinas/síntesis química , Isoquinolinas/química , Cinética , Microsomas Hepáticos/enzimología , Estructura Molecular , Unión Proteica , Ratas , Escualeno/análogos & derivados , Escualeno/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of glycosylated derivatives of benzophenone, benzhydrol, and benzhydril has been synthesized and evaluated for potential activity as venous antithrombotic agents. Studies on structure-activity relationships revealed that compounds having an electron-withdrawing group in the benzhydril or benzhydrol moiety, and specifically those having the beta-D-xylopyranosyl structure in the sugar moiety, were good antithrombotic agents in a rat model of venous thrombosis.