title: Triterpenoids as novel natural inhibitors of human cathepsin L.
abstract: Cathepsins L (catL) and B play an important role in tumor progression and have been considered promising therapeutic targets in the development of novel anticancer agents. Using a bioactivity-guided fractionation, a series of triterpenoids was identified as a new class of competitive inhibitors towards cathepsin L with affinity values in micromolar range. Among the 14 compounds evaluated, the most promising were 3-epiursolic acid (3), 3-(hydroxyimino)oleanolic acid (9), and 3-(hydroxyimino)masticadienoic acid (13) with IC50 values of 6.5, 2.4, and 2.6 μM on catL, respectively. Most of the evaluated triterpenoids do not inhibit cathepsin B. Thus, the evaluated compounds exhibit a great potential to help in the design of new inhibitors with enhanced potency and affinity towards catL. Docking studies were performed in order to gain insight on the binding mode and SAR of these compounds.
authors.affiliation: Department of Chemistry, Federal University of São Carlos, 13565-905 São Carlos, SP, Brazil, (phone: +55-16-33518061; fax: +55-16-33518350).
authors.forename: Suelem D
authors.initials: SD
authors.lastname: Ramalho
authors.forename: Lorena R F
authors.initials: LR
authors.lastname: De Sousa
authors.forename: Liliane
authors.initials: L
authors.lastname: Nebo
authors.forename: Stella H
authors.initials: SH
authors.lastname: Maganhi
authors.forename: Ignez
authors.initials: I
authors.lastname: Caracelli
authors.forename: Julio
authors.initials: J
authors.lastname: Zukerman-Schpector
authors.forename: Maria Inês S
authors.initials: MI
authors.lastname: Lima
authors.forename: Marcio F M
authors.initials: MF
authors.lastname: Alves
authors.forename: M Fátima das G F
authors.initials: MF
authors.lastname: Da Silva
authors.forename: João B
authors.initials: JB
authors.lastname: Fernandes
authors.forename: Paulo C
authors.initials: PC
authors.lastname: Vieira
mesh_terms: D056668:Cathepsin L / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D062105:Molecular Docking Simulation; D027822:Myrtaceae / Q000737:chemistry; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D014315:Triterpenes; D056668:Cathepsin L
keywords: Cathepsin L; Inhibitors; Triterpenoids