title: Natural polyprenylated benzophenones inhibiting cysteine and serine proteases.
abstract: We have investigated the in vitro inhibition of papain, trypsin, and cathepsins B and G by five benzophenone-type compounds, three natural ones isolated from Garcinia brasiliensis and two synthetic derivatives. The activities of pentaprenylated trihydroxy-substituted benzophenone guttiferone A (1) on all assayed enzymes were approximately 2-69 folds higher than that manifested by mono-hydroxylated tetraprenylated and triprenylated compounds epiclusianone (2) and garciniaphenone (3), respectively, the other natural benzophenones that also inhibited significantly the four enzymes. Differently, the synthetic derivatives 2,2',4-trihydroxybenzophenone (4) and diphenylmethanone (5) have inhibited weakly the studied proteases. Furthermore, compound 1 has bonded preferentially to cathepsin G, once its IC(50) value (2.7+/-0.1 microM) on such peptidase is quite similar to that of the classical inhibitor of serine proteases, chymostatin (2.1+/-0.1 microM). Interesting structure-activity relationships (SARs) were confirmed by flexible docking simulations, likewise the potential usefulness of natural compound 1 as antitumoral drug is strengthened by our results concerning the antiproteolytic activity.
authors.affiliation: Department of Exact Science, Federal University of Alfenas, Rua Gabriel Monteiro da Silva 714, Alfenas, MG 37130-000, Brazil. felipetmartins@yahoo.com.br
authors.forename: Felipe T
authors.initials: FT
authors.lastname: Martins
authors.forename: Diego M
authors.initials: DM
authors.lastname: Assis
authors.forename: Marcelo H
authors.initials: MH
authors.lastname: Dos Santos
authors.forename: I
authors.initials: I
authors.lastname: Camps
authors.forename: Márcia P
authors.initials: MP
authors.lastname: Veloso
authors.forename: Maria A
authors.initials: MA
authors.lastname: Juliano
authors.forename: Lira C
authors.initials: LC
authors.lastname: Alves
authors.forename: Antônio C
authors.initials: AC
authors.lastname: Doriguetto
mesh_terms: D001577:Benzophenones / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013057:Spectrum Analysis / Q000379:methods
chemical_list: D001577:Benzophenones; D015853:Cysteine Proteinase Inhibitors; D015842:Serine Proteinase Inhibitors