title: Hydroxyethylene sulfones as a new scaffold to address aspartic proteases: design, synthesis, and structural characterization.
abstract: Hydroxyethylene sulfones were developed as novel scaffolds against aspartyl proteases. A diastereoselective synthesis has been established to introduce the required side chain decoration with desired stereochemistry. Depending on the substitution of the hydroxyethylene sulfone core, micro- to submicromolar inhibition of HIV-1 protease is achieved for the S-configuration at P1 and R-configuration at the hydroxy-group-bearing backbone atom. This stereochemical preference is consistent with the S,R configuration of amprenavir. The racemic mixture of the most potent derivative (K(i) = 80 nM) was separated by chiral HPLC, revealing the S,R,S-enantiomer to be more active (K(i) = 45 nM). Docking studies suggested this isomer as the more active one. The subsequently determined crystal structure with HIV-1 protease, cocrystallized from a racemic mixture, exclusively reveals the S,R,S-enantiomer accommodated to the binding pocket. The transition state mimicking hydroxy group of the inhibitor is centered between both catalytic aspartates, while either its carbonyl or sulfonyl group forms H-bonds to the structurally conserved water mediating interactions between ligand and Ile50NH/Ile50NH' of both flaps. Biological testing of the stereoisomeric hydroxyethylene sulfones against cathepsin D and beta-secretase did not reveal significant inhibition. Most likely, the latter proteases require inverted configuration at the hydroxy group.
authors.affiliation: Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marbacher Weg 6, D-35032 Marburg, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Specker
authors.forename: Jark
authors.initials: J
authors.lastname: Böttcher
authors.forename: Andreas
authors.initials: A
authors.lastname: Heine
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Sotriffer
authors.forename: Hauke
authors.initials: H
authors.lastname: Lilie
authors.forename: Andreas
authors.initials: A
authors.lastname: Schoop
authors.forename: Gerhard
authors.initials: G
authors.lastname: Müller
authors.forename: Nils
authors.initials: N
authors.lastname: Griebenow
authors.forename: Gerhard
authors.initials: G
authors.lastname: Klebe
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005030:Ethylenes / Q000138:chemical synthesis* / Q000737:chemistry; D016333:HIV Protease / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D005030:Ethylenes; D011480:Protease Inhibitors; D013450:Sulfones; D016333:HIV Protease