title: Structure-activity relationships: analogues of the dicaffeoylquinic and dicaffeoyltartaric acids as potent inhibitors of human immunodeficiency virus type 1 integrase and replication.
abstract: The dicaffeoylquinic acids (DCQAs) and dicaffeoyltartaric acids (DCTAs) are potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) integrase. They also inhibit HIV-1 replication at nontoxic concentrations. Since integrase is an excellent target for anti-HIV therapy, structure-activity relationships were employed to synthesize compounds with: (1) improved potency against HIV-1 integrase, (2) improved anti-HIV effect in tissue culture, and (3) increased selectivity as indicated by low cellular toxicity. Thirty-four analogues of the DCTAs and DCQAs were synthesized and tested for cell toxicity, anti-HIV activity, and inhibition of HIV-1 integrase. Seventeen of the 34 analogues had potent activity against HIV-1 integrase ranging from 0. 07 to >10 microM. Seventeen analogues that were synthesized or purchased had no inhibitory activity against integrase at concentrations of 25 microM. Of the biologically active analogues, 7 of the 17 inhibited HIV replication at nontoxic concentrations. The most potent compounds were D-chicoric acid, meso-chicoric acid, bis(3,4-dihydroxydihydrocinnamoyl)-L-tartaric acid, digalloyl-L-tartaric acid, bis(3,4-dihydroxybenzoyl)-L-tartaric acid, dicaffeoylglyceric acid, and bis(3, 4-dihydroxyphenylacetyl)-L-tartaric acid. Anti-HIV activity of the active compounds in tissue culture ranged from 35 to 0.66 microM. Structure-activity relationships demonstrated that biscatechol moieties were absolutely required for inhibition of integrase, while at least one free carboxyl group was required for anti-HIV activity. These data demonstrate that analogues of the DCTAs and the DCQAs can be synthesized which have improved activity against HIV integrase.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697-4800, USA.
authors.forename: P J
authors.initials: PJ
authors.lastname: King
authors.forename: G
authors.initials: G
authors.lastname: Ma
authors.forename: W
authors.initials: W
authors.lastname: Miao
authors.forename: Q
authors.initials: Q
authors.lastname: Jia
authors.forename: B R
authors.initials: BR
authors.lastname: McDougall
authors.forename: M G
authors.initials: MG
authors.lastname: Reinecke
authors.forename: C
authors.initials: C
authors.lastname: Cornell
authors.forename: J
authors.initials: J
authors.lastname: Kuan
authors.forename: T R
authors.initials: TR
authors.lastname: Kim
authors.forename: W E
authors.initials: WE
authors.lastname: Robinson
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D002109:Caffeic Acids; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002726:Chlorogenic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D003001:Cloning, Molecular; D017931:DNA Primers; D004352:Drug Resistance, Microbial / Q000235:genetics; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship; D013386:Succinates; D013644:Tartrates / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*