Design, synthesis, and preliminary biological evaluation of pyrrolo[3,4-c]quinolin-1-one and oxoisoindoline derivatives as aggrecanase inhibitors.
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.
Cappelli
Andrea
A
Dipartimento Farmaco Chimico Tecnologico and the European Research Centre for Drug Discovery and Development, Università di Siena, Italy. cappelli@unisi.it <cappelli@unisi.it>
Nannicini
Chiara
C
Valenti
Salvatore
S
Giuliani
Germano
G
Anzini
Maurizio
M
Mennuni
Laura
L
Giordani
Antonio
A
Caselli
Gianfranco
G
Stasi
Luigi Piero
LP
Makovec
Francesco
F
Giorgi
Gianluca
G
Vomero
Salvatore
S
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
D007211:Indoles; D011480:Protease Inhibitors; D015363:Quinolones; C057812:indoline; D010450:Endopeptidases; D051722:ADAM Proteins; C083641:aggrecanase