2. Academic Validation
  3. Synthesis and biological evaluation of new C-10 substituted dithranol pleiotropic hybrids

Synthesis and biological evaluation of new C-10 substituted dithranol pleiotropic hybrids

  • Bioorg Med Chem. 2015 Nov 15;23(22):7251-63. doi: 10.1016/j.bmc.2015.10.022.
Stavros E Bariamis 1,  George E Magoulas 1,  Katerina Grafanaki 2,  Eleni Pontiki 3,  Theodore Tsegenidis 1,  Constantinos M Athanassopoulos 1,  George Maroulis 1,  Dionissios Papaioannou 4,  Dimitra Hadjipavlou-Litina 5
Affiliations

Affiliations

  • 1 Department of Chemistry, School of Natural Sciences, University of Patras, 26504 Patras, Greece.
  • 2 Laboratory of Biochemistry, Department of Medicine, School of Health Sciences, University of Patras, 26504 Patras, Greece.
  • 3 Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
  • 4 Department of Chemistry, School of Natural Sciences, University of Patras, 26504 Patras, Greece. Electronic address: dapapaio@chemistry.upatras.gr.
  • 5 Department of Pharmaceutical Chemistry, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece. Electronic address: hadjipav@pharm.auth.gr.
PMID: 26515039 DOI: 10.1016/j.bmc.2015.10.022
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.

Keywords

Amides; Anti-inflammatory activity; Antioxidant activity; Antiproliferative activity; Dithranol; Polyamines.

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