Small, potent, and selective diaryl phosphonate inhibitors for urokinase-type plasminogen activator with in vivo antimetastatic properties.
A set of small nonpeptidic diaryl phosphonate inhibitors was prepared. Some of these inhibitors show potent and highly selective irreversible uPA inhibition. The biochemical and modeling data prove that the combination of a benzylguanidine moiety with a diaryl phosphonate ester results in optimized molecules for derivatizing the serine alcohol in the uPA active site. Selected compounds show significant antimetastatic effects in the BN-472 rat mammary carcinoma model. We report in this paper a preclinical proof of concept that selective, irreversible uPA inhibitors could be valuable in antimetastatic therapy.
Joossens
Jurgen
J
Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium.
Ali
Omar M
OM
El-Sayed
Ibrahim
I
Surpateanu
Georgiana
G
Van der Veken
Pieter
P
Lambeir
Anne-Marie
AM
Setyono-Han
Buddy
B
Foekens
John A
JA
Schneider
Anneliese
A
Schmalix
Wolfgang
W
Haemers
Achiel
A
Augustyns
Koen
K
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006146:Guanidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000473:pathology; D008958:Models, Molecular; D009362:Neoplasm Metastasis; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D006146:Guanidines; D063065:Organophosphonates; C527724:methyl 1-(bis(4-acetamidophenoxy)phosphoryl)-2-(4-guanidinophenyl)ethylcarbamate; C527723:methyl 1-(diphenoxyphosphoryl)-2-(4-guanidinophenyl)ethylcarbamate; D014568:Urokinase-Type Plasminogen Activator