title: Curcumin analogs with altered potencies against HIV-1 integrase as probes for biochemical mechanisms of drug action.
abstract: We have previously reported the inhibitory activity of curcumin against human immunodeficiency virus type one (HIV-1) integrase. In the present study, we have synthesized and tested analogs of curcumin to explore the structure-activity relationships and mechanism of action of this family of compounds in more detail. We found that two curcumin analogs, dicaffeoylmethane (6) and rosmarinic acid (9), inhibited both activities of integrase with IC50 values below 10 microM. We have previously demonstrated that lysine 136 may play a role in viral DNA binding. We demonstrated equivalent potencies of two curcumin analogs against both this integrase mutant and wild-type integrase, suggesting that the curcumin-binding site and the substrate-binding site may not overlap. Combining one curcumin analog with the recently described integrase inhibitor NSC 158393 resulted in integrase inhibition which was synergistic, reflective of drug-binding sites which may not overlap. We have also determined that these analogs can inhibit binding of the enzyme to the viral DNA but that this inhibition is independent of divalent metal ion. Furthermore, kinetic studies of these analogs suggest that they bind to the enzyme at a slow rate. These studies can provide mechanistic and structural information which may guide the future design of integrase inhibitors.
authors.affiliation: Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland 20892, USA.
authors.forename: A
authors.initials: A
authors.lastname: Mazumder
authors.forename: N
authors.initials: N
authors.lastname: Neamati
authors.forename: S
authors.initials: S
authors.lastname: Sunder
authors.forename: J
authors.initials: J
authors.lastname: Schulz
authors.forename: H
authors.initials: H
authors.lastname: Pertz
authors.forename: E
authors.initials: E
authors.lastname: Eich
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
mesh_terms: D015110:4-Hydroxycoumarins / Q000494:pharmacology; D001483:Base Sequence; D002396:Catechols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002934:Cinnamates / Q000494:pharmacology; D003474:Curcumin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004279:DNA, Viral / Q000737:chemistry / Q000378:metabolism; D053630:Depsides; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D000097123:Rosmarinic Acid
chemical_list: D015110:4-Hydroxycoumarins; D002396:Catechols; D002934:Cinnamates; D003474:Curcumin; D004279:DNA, Viral; D053630:Depsides; D019427:HIV Integrase; D019428:HIV Integrase Inhibitors; D009838:Oligodeoxyribonucleotides; D000097123:Rosmarinic Acid; C100452:NSC 158393