Synthesis and biological evaluation of new C-10 substituted dithranol pleiotropic hybrids. Issue 22 (15th November 2015)

• Record Type: Journal Article
• Authors: Bariamis, Stavros E.; Magoulas, George E.; Grafanaki, Katerina; Pontiki, Eleni; Tsegenidis, Theodore; Athanassopoulos, Constantinos M.; Maroulis, George; Papaioannou, Dionissios; Hadjipavlou-Litina, Dimitra
• Is Part Of: Bioorganic & medicinal chemistry. Volume 23:Issue 22(2015)
• Page Start: 7251
• Page End: 7263
• Publication Date: 2015-11-15
• Subjects: AAPH 2, 2-azobis(2-amidinopropane) dihydrochloride -- Boc tert-butyloxycarbonyl -- DPPH 1, 1-diphenyl-2-picrylhydrazyl radical -- ET single electron transfer -- FCC Flash Column Chromatography -- HAT hydrogen atom transfer -- LOX lipoxygenase -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- NDGA nordihydroguaiaretic acid -- PA(s) polyamine(s) -- PUT putrescine -- PyBrOP bromotripyrrolidinophosphonium hexafluorophosphate -- ROS Reactive Oxygen Species -- SPD spermidine -- SPM spermine -- TFA trifluoroacetic acid -- Trt trityl(triphenylmethyl); Dithranol -- Polyamines -- Amides -- Antioxidant activity -- Anti-inflammatory activity -- Antiproliferative activity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.10.022
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: 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 acid4 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′-dimethoxybenzhydrylamide13 (86% and 95%), 2, 4-dimethoxybenzylamide12 (87% and 81%) and dodecylamide9 (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 amide13 (IC50 = 7 μM), the benzylamide10 (IC50 = 7.9 μM) and the butylamide8 (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. Amide13 presented the highest anti-inflammatory activity (79.7%). The DTR moiety was absolutely necessary for securing high anti-inflammatory potency. Ethyl ester3 (IC50 = 0.357 μM) and the amides9 (IC50 = 0.022 μM) and13 (IC50 = 0.56 μM) exhibited higher antiproliferative activity than DTR (IC50 = 0.945 μM) on HaCaT keratinocytes whereas amide13 generally presented better cytocompatibility. Amide13 is a very promising lead compound for further development as an anti-inflammatory and antiproliferative agent.