title: Design, synthesis, and preliminary biological evaluation of pyrrolo[3,4-c]quinolin-1-one and oxoisoindoline derivatives as aggrecanase inhibitors.
abstract: A small set of aggrecanase inhibitors based on the pyrrolo[3,4-c]quinolin-1-one or oxoisoindoline frameworks bearing a 4-(benzyloxy)phenyl substituent and different zinc binding groups were rationally designed and evaluated in silico by docking studies using the crystal structure of the ADAMTS-5 catalytic domain (PDB code: 3B8Z). The designed compounds were synthesized via straightforward routes and tested for their potential inhibitory activity against ADAMTS-5 and ADAMTS-4. Among the compounds containing the pyrrolo[3,4-c]quinolinone tricyclic system, hydroxamate derivative 2 b inhibited both ADAMTS-5 and ADAMTS-4, with IC(50) values in the submicromolar range and an inhibitory profile very similar to that of reference carboxylate derivative 11. Conversely, the corresponding carboxylate derivative 2 a was significantly less active and unable to discriminate between ADAMTS-5 and -4. The structure-activity relationship analysis of pyrroloquinolinone derivatives 2 a-i suggests that the carboxylate or hydroxamate groups of compounds 2 a,b play a key role in the interaction of these compounds with ADAMTS-5 and -4. On the other hand, the oxoisoindoline derivatives 3 a,b lack significant ADAMTS-4 inhibitory activity and inhibit ADAMTS-5 showing IC(25) values in the micromolar range.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico and the European Research Centre for Drug Discovery and Development, Università di Siena, Italy. cappelli@unisi.it <cappelli@unisi.it>
authors.forename: Andrea
authors.initials: A
authors.lastname: Cappelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Nannicini
authors.forename: Salvatore
authors.initials: S
authors.lastname: Valenti
authors.forename: Germano
authors.initials: G
authors.lastname: Giuliani
authors.forename: Maurizio
authors.initials: M
authors.lastname: Anzini
authors.forename: Laura
authors.initials: L
authors.lastname: Mennuni
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordani
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Caselli
authors.forename: Luigi Piero
authors.initials: LP
authors.lastname: Stasi
authors.forename: Francesco
authors.initials: F
authors.lastname: Makovec
authors.forename: Gianluca
authors.initials: G
authors.lastname: Giorgi
authors.forename: Salvatore
authors.initials: S
authors.lastname: Vomero
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D010450:Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D007211:Indoles; D011480:Protease Inhibitors; D015363:Quinolones; C057812:indoline; D010450:Endopeptidases; D051722:ADAM Proteins; C083641:aggrecanase