title: Synthesis and evaluation of the antioxidative potential of minoxidil-polyamine conjugates.
abstract: A series of conjugates (MNX-CO-PA) of minoxidil (MNX) with the polyamines (PAs) putrescine (PUT), spermidine (SPD) and spermine (SPM) as well as dopamine were produced through activation of MNX with N,N'-carbonyldiimidazole, followed by reaction with dopamine or selectively protected PAs and acid-mediated deprotection. These conjugates together with conjugates of the general type MNX-PA or PA-MNX-PA, readily produced using literature protocols, were tested as antioxidants. The most potent inhibitors of lipid peroxidation were the conjugates MNX-SPM (2, 94%), SPM-MNX-SPM (4, 94%) and MNX-N(4)-SPD (7, 91%) and MNX (91%). The most powerful lipoxygenase (LOX) inhibitors were MNX (IC50 = 20 μM) and the conjugates MNX-N(8)-SPD (9, IC50 = 22.1 μM), MNX-CO-dopamine (11, IC50 = 28 μM) and MNX-N(1)-SPD (8, IC50 = 30 μM). The most interesting conjugates 2, MNX-CO-PUT (5), 8 and 11 as well as MNX were generally found to exhibit weaker (22-36.5%) or no (conjugate 8) anti-inflammatory activity than indomethacin (47%) with the exception of MNX which showed almost equal potency (49%) to indomethacin. The cytocompatibility of conjugates and MNX at the highest concentration of 100 μM showed a survival percentage of 87-107%, with the exception of conjugates with SPM (compound 2) and MNX-CO-SPM (6), which showed considerable cytotoxicity (survival percentage 8-14%). Molecular docking studies were carried on conjugate 9 and the parent compound MNX and were found to be in accordance with our experimental biological results.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. hadjipav@pharm.auth.gr
authors.forename: Dimitra
authors.initials: D
authors.lastname: Hadjipavlou-Litina
authors.forename: George E
authors.initials: GE
authors.lastname: Magoulas
authors.forename: Stavros E
authors.initials: SE
authors.lastname: Bariamis
authors.forename: Zinovia
authors.initials: Z
authors.lastname: Tsimali
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Avgoustakis
authors.forename: Christos A
authors.initials: CA
authors.lastname: Kontogiorgis
authors.forename: Constantinos M
authors.initials: CM
authors.lastname: Athanassopoulos
authors.forename: Dionissios
authors.initials: D
authors.lastname: Papaioannou
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000975:Antioxidants / Q000138:chemical synthesis* / Q000494:pharmacology; D005260:Female; D008297:Male; D008914:Minoxidil / Q000138:chemical synthesis* / Q000494:pharmacology; D011073:Polyamines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D011073:Polyamines; D008914:Minoxidil