153223-23-5Relevant articles and documents
Grignard addition to aldonitrones. Stereochemical aspects and application to the synthesis of C2-symmetric diamino alcohols and diamino diols
Dondoni, Alessandro,Perrone, Daniela,Rinaldi, Marilisa
, p. 9252 - 9264 (2007/10/03)
A new example of the stereoselective installation of the amino group at a saturated carbon center via organometallic addition of chiral aldehydes to nitrones is illustrated by the synthesis of 1,3-diamino propanol 1 and 1,4- diamino butandiol 2 units. Three diamino alcohol 1 stereotriads were obtained by stereoselective addition of alkylmagnesium halides (benzyl, cyclohexylmethyl, and metallyl) to the N-benzyl nitrones derived from β- amino-α-hydroxy aldehydes followed by reduction of the resulting N- benzylhydroxylamines. Three 1,4-dibenzyl substituted stereoisomers of type 2 with fixed S configuration at C2 and C3 were prepared by sequential and simultaneous amination in two directions starting from L-threose nitrone and L-tartraldehyde bis-nitrone, respectively. The R,S,S,R isomer obtained by the former route was converted into a seven-membered ring cyclic urea (1,3- diazapin-2-one), i.e., a compound that belongs to a class of nonpeptide HIV- 1 protease inhibitors.
Cyclic HIV protease inhibitors: Synthesis, conformational analysis, P2/P2' structure-activity relationship, and molecular recognition of cyclic ureas
Lam, Patrick Y. S.,Ru, Yu,Jadhav, Prabhakar K.,Aldrich, Paul E.,DeLucca, George V.,Eyermann, Charles J.,Chang, Chong-Hwan,Emmett, George,Holler, Edward R.,Daneker, Wayne F.,Li, Liangzhu,Confalone, Pat N.,McHugh, Robert J.,Han, Qi,Li, Renhua,Markwalder, Jay A.,Seitz, Steven P.,Sharpe, Thomas R.,Bacheler, Lee T.,Rayner, Marlene M.,Klabe, Ronald M.,Shum, Linyee,Winslow, Dean L.,Kornhauser, David M.,Jackson, David A.,Erickson-Viitanen, Susan,Hodge, C. Nicholas
, p. 3514 - 3525 (2007/10/03)
High-resolution X-ray structures of the complexes of HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal the presence of a structural water molecule which is hydrogen bonded to both the mobile flaps of the enzyme and the two carbonyls flanking
Preparation and structure-activity relationship of novel P1/P1'- substituted cyclic urea-based human immunodeficiency virus type-1 protease inhibitors
Nugiel,Jacobs,Worley,Patel,Kaltenbach III,Meyer,Jadhav,De Lucca,Smyser,Klabe,Bacheler,Rayner,Seitz
, p. 2156 - 2169 (2007/10/03)
A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.
