New N-arylsulfonyl-N-alkoxyaminoacetohydroxamic acids as selective inhibitors of gelatinase A (MMP-2).
New N-arylsulfonyl-substituted alkoxyaminoaceto hydroxamic acid derivatives of types 8 and 10 designed as oxa-analogues of known sulfonamide-based MMPi of types 2 and 7 were synthesized and tested for their inhibitory activities on some matrix metalloproteinases. The combination of a biphenylsulfonamide group with oxyamino oxygen in the pharmacophoric central skeleton of sulfonamide-based MMPi obtained in the new sulfonamides 10 seems to be able to give selectivity for MMP-2 over MMP-1. The most potent derivative of this type, 10a, shows similar anti-invasive properties to the analogue reference drug CGS27023A, 2, in an in vitro model of invasion on matrigel, carried out on cellular lines of fibrosarcoma HT1080 (tumoural cells over-expressing MMP-2 and MMP-9).
Rossello
Armando
A
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Pisa, Via Bonanno, 6, 56126 Pisa, Italy. aros@farm.unipi.it
Nuti
Elisa
E
Orlandini
Elisabetta
E
Carelli
Paolo
P
Rapposelli
Simona
S
Macchia
Marco
M
Minutolo
Filippo
F
Carbonaro
Laura
L
Albini
Adriana
A
Benelli
Roberto
R
Cercignani
Giovanni
G
Murphy
Gillian
G
Balsamo
Aldo
A
D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020778:Matrix Metalloproteinase 2