title: Design of barbiturate-nitrate hybrids that inhibit MMP-9 activity and secretion.
abstract: We describe a new type of barbiturate-based matrix metalloproteinase (MMP) inhibitor incorporating a nitric oxide (NO) donor/mimetic group (series 1). The compounds were designed to inhibit MMP at enzyme level and to attenuate MMP-9 secretion arising from inflammatory signaling. To detect effects related to the nitrate, we prepared and studied an analogous series of barbiturate C5-alkyl alcohols that were unable to release NO (series 2). Both series inhibited recombinant human MMP-2/9 activity with nanomolar potency. Series 1 consistently inhibited the secretion of MMP-9 from TNFα/IL1β stimulated Caco-2 cells at 10 μM, which could be attributed to NO related effects because the non-nitrate panel did not affect enzyme levels. Several compounds from series 1 (10 μM) inhibited tumor cell invasion but none from the non-nitrate panel did. The work shows that MMP-inhibitory barbiturates are suitable scaffolds for hybrid design, targeting additional facets of MMP pathophysiology, with potential to improve risk-benefit ratios.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Shane
authors.initials: S
authors.lastname: O'Sullivan
authors.forename: Shona
authors.initials: S
authors.lastname: Harmon
authors.forename: Ray
authors.initials: R
authors.lastname: Keaveny
authors.forename: Marek W
authors.initials: MW
authors.lastname: Radomski
authors.forename: Carlos
authors.initials: C
authors.lastname: Medina
authors.forename: John F
authors.initials: JF
authors.lastname: Gilmer
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001463:Barbiturates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen; D004338:Drug Combinations; D015195:Drug Design; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology; D007797:Laminin; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D018716:Molecular Mimicry; D009361:Neoplasm Invasiveness; D020030:Nitric Oxide Donors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011509:Proteoglycans; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D001463:Barbiturates; D004338:Drug Combinations; D053583:Interleukin-1beta; D007797:Laminin; D061965:Matrix Metalloproteinase Inhibitors; D020030:Nitric Oxide Donors; D011509:Proteoglycans; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C059485:matrigel; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9