RESUMEN
The synthesis and stereochemical determination of 1-(4-(4-((1R,5R,6R)-6-hydroxy-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-6-morpholino-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea (2), an active metabolite of the potent PI3 kinase inhibitor PKI-179 (1), is described. Stereospecific hydroboration of the double bond of 2,5-dihydro-1H-pyrrole 8 gave the 2,3-trans alcohol 9 exclusively. The configuration of the 3-hydroxyl group in 9 was inverted by an oxidation and stereoselective reduction sequence to give the corresponding 2,3-cis isomer 23. Both exo (21) and endo (27) isomers of the metabolite 2 were prepared via a practical synthetic route from 9 and 23, respectively, and the stereochemistry of 2 was determined to be endo. The endo isomer (27) was separated into two enantiomers 28 and 29 by chiral HPLC. Compound 2 was found to be enantiomerically pure and identical to the enantiomer 28. The absolute stereochemistry of the enantiomer 28 was determined by Mosher's method, thus establishing the stereochemistry of the active metabolite 2.
Asunto(s)
Hidrocarburos Aromáticos con Puentes/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/síntesis química , Morfolinas/síntesis química , Inhibidores de las Quinasa Fosfoinosítidos-3 , Urea/análogos & derivados , Sitios de Unión , Hidrocarburos Aromáticos con Puentes/química , Inhibidores Enzimáticos/farmacología , Estructura Molecular , Morfolinas/química , Morfolinas/farmacología , Oxidación-Reducción , Fosfatidilinositol 3-Quinasas/química , Estereoisomerismo , Urea/síntesis química , Urea/química , Urea/farmacologíaRESUMEN
The effect of introducing hydrophobic groups onto the disaccharide portion of the mannopeptimycins has been examined. Under acid-catalyzed conditions dimethyl acetals and ketals react on the terminal mannose of the disaccharide moiety of mannopeptimycin-alpha and the cyclohexylalanyl analogue 2. The preferentially formed monofunctionalized 4,6-acetals and -ketals display potent antibacterial activities against Gram-positive microorganisms, including MRSA, PRSP, and VRE pathogens.
Asunto(s)
Acetales/síntesis química , Antibacterianos/síntesis química , Glicopéptidos , Bacterias Grampositivas/efectos de los fármacos , Acetales/química , Acetales/farmacología , Antibacterianos/química , Antibacterianos/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Espectrometría de Masa por Ionización de Electrospray , Relación Estructura-ActividadRESUMEN
A number of 6-O-ether and 4-O-ether derivatives of mannopeptimycin-alpha with different steric bulk and lipophilicity were synthesized for structure-activity relationship study. Novel iodo and bromo mannopeptimycin-alpha were also prepared. These compounds were synthesized via electrophilic aromatic substitution. Many of the new ether derivatives exhibited potent antibacterial activity against Gram-positive resistant strains including VRE, MRSA, and PRSP.