title: Synthesis and biological evaluation of new C-10 substituted dithranol pleiotropic hybrids.
abstract: Selective alkylation of the antipsoriatic drug dithranol (DTR) at C-10 with tert-butyl bromoacetate, followed by acid-mediated deprotection, produced the corresponding carboxylic acid 4 which was coupled with selectively protected polyamines (PAs), such as putrescine (PUT), spermidine (SPD) and spermine (SPM), dopamine and aliphatic amines and substituted benzylamines producing a series of DTR-PA hybrids, after acid-mediated deprotection, as well as simple amides. The compounds were tested as antioxidants and inhibitors of lipoxygenase (LOX). The amides 4,4'-dimethoxybenzhydrylamide 13 (86% and 95%), 2,4-dimethoxybenzylamide 12 (87% and 81%) and dodecylamide 9 (98% and 74%), and the hybrid DTR-SPM (7) (93% and 87%), showed the highest antioxidant activity in the DPPH and AAPH assays, whereas the most potent inhibitors of LOX were amide 13 (IC50=7 μM), the benzylamide 10 (IC50=7.9 μM) and the butylamide 8 (IC50=10 μM). Molecular binding studies showed that binding of these derivatives into the hydrophobic domain blocks approach of substrate to the active site, inhibiting soybean LOX. Amide 13 presented the highest anti-inflammatory activity (79.7%). The DTR moiety was absolutely necessary for securing high anti-inflammatory potency. Ethyl ester 3 (IC50=0.357 μM) and the amides 9 (IC50=0.022 μM) and 13 (IC50=0.56 μM) exhibited higher antiproliferative activity than DTR (IC50=0.945 μM) on HaCaT keratinocytes whereas amide 13 generally presented better cytocompatibility. Amide 13 is a very promising lead compound for further development as an anti-inflammatory and antiproliferative agent.
authors.affiliation: Department of Chemistry, School of Natural Sciences, University of Patras, 26504 Patras, Greece.
authors.forename: Stavros E
authors.initials: SE
authors.lastname: Bariamis
authors.affiliation: Department of Chemistry, School of Natural Sciences, University of Patras, 26504 Patras, Greece.
authors.forename: George E
authors.initials: GE
authors.lastname: Magoulas
authors.affiliation: Laboratory of Biochemistry, Department of Medicine, School of Health Sciences, University of Patras, 26504 Patras, Greece.
authors.forename: Katerina
authors.initials: K
authors.lastname: Grafanaki
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Pontiki
authors.affiliation: Department of Chemistry, School of Natural Sciences, University of Patras, 26504 Patras, Greece.
authors.forename: Theodore
authors.initials: T
authors.lastname: Tsegenidis
authors.affiliation: Department of Chemistry, School of Natural Sciences, University of Patras, 26504 Patras, Greece.
authors.forename: Constantinos M
authors.initials: CM
authors.lastname: Athanassopoulos
authors.affiliation: Department of Chemistry, School of Natural Sciences, University of Patras, 26504 Patras, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Maroulis
authors.affiliation: Department of Chemistry, School of Natural Sciences, University of Patras, 26504 Patras, Greece. Electronic address: dapapaio@chemistry.upatras.gr.
authors.forename: Dionissios
authors.initials: D
authors.lastname: Papaioannou
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. Electronic address: hadjipav@pharm.auth.gr.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Hadjipavlou-Litina
mesh_terms: D000577:Amides / Q000737:chemistry; D000818:Animals; D000875:Anthralin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D002351:Carrageenan / Q000633:toxicity; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004487:Edema / Q000209:etiology / Q000517:prevention & control; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects; D008084:Lipoxygenase / Q000737:chemistry / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D062105:Molecular Docking Simulation; D011073:Polyamines / Q000737:chemistry; D051381:Rats; D013025:Glycine max / Q000201:enzymology
chemical_list: D000577:Amides; D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D016859:Lipoxygenase Inhibitors; D011073:Polyamines; D002351:Carrageenan; D008084:Lipoxygenase; D000875:Anthralin
keywords: Amides; Anti-inflammatory activity; Antioxidant activity; Antiproliferative activity; Dithranol; Polyamines