title: Dicaffeoyltartaric acid analogues inhibit human immunodeficiency virus type 1 (HIV-1) integrase and HIV-1 replication at nontoxic concentrations.
abstract: The human immunodeficiency virus type 1 (HIV-1) is a major health problem worldwide. In this study, 17 analogues of L-chicoric acid, a potent inhibitor of HIV integrase, were studied. Of these analogues, five submicromolar inhibitors of integrase were discovered and 13 compounds with activity against integrase at less than 10 microM were identified. Six demonstrated greater than 10-fold selectivity for HIV replication over cellular toxicity. Ten analogues inhibited HIV replication at nontoxic concentrations. Alteration of the linkages between the two bis-catechol rings, including the use of amides, mixed amide esters, cholate, and alkyl bridges, was explored. Amides were as active as esters but were more toxic in tissue culture. Alkyl and cholate bridges were significantly less potent against HIV-1 integrase in vitro and were inactive against HIV-1 replication. Two amino acid derivates and one digalloylderivative of L-chicoric acid (L-CA) showed improved selectivity over L-CA against integration in cell culture. These data suggest that in addition to the bis-catechols and free carboxylic acid groups reported previously, polar linkages are important constituents for optimal activity against HIV-1 integrase and that new derivatives can be developed with increased specificity for integration over HIV entry in vivo.
authors.affiliation: Department of Microbiology & Molecular Genetics, Pathology, and Medicine, University of California, Irvine, California 92697, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Reinke
authors.forename: Peter J
authors.initials: PJ
authors.lastname: King
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Victoria
authors.forename: Brenda R
authors.initials: BR
authors.lastname: McDougall
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Ma
authors.forename: Yingqun
authors.initials: Y
authors.lastname: Mao
authors.forename: Manfred G
authors.initials: MG
authors.lastname: Reinecke
authors.forename: W Edward
authors.initials: WE
authors.lastname: Robinson
mesh_terms: D001565:Benzoates / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D002109:Caffeic Acids; D002470:Cell Survival / Q000187:drug effects; D002726:Chlorogenic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D006868:Hydrolysis; D013329:Structure-Activity Relationship; D013386:Succinates / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity; D013644:Tartrates / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D014779:Virus Replication / Q000187:drug effects
chemical_list: D001565:Benzoates; D002109:Caffeic Acids; D019428:HIV Integrase Inhibitors; D013386:Succinates; D013644:Tartrates; D002726:Chlorogenic Acid; C100435:chicoric acid