title: Selective growth inhibition of human malignant melanoma cells by syringic acid-derived proteasome inhibitors.
abstract: BACKGROUND
  It has been shown that proteasome inhibition leads to growth arrest in the G1 phase of the cell cycle and/or induction of apoptosis. However, it was found that some of these inhibitors do not induce apoptosis in several human normal cell lines. This selective activity makes proteasome inhibition a promising target for new generation of anticancer drugs. Clinical validation of the proteasome, as a therapeutic target in oncology, has been provided by the dipeptide boronic acid derivative; bortezomib. Bortezomib has proven to be effective as a single agent in multiple myeloma and some forms of non-Hodgkin's lymphoma. Syringic acid (4-hydroxy-3,5-dimethoxybenzoic acid, 1), a known phenolic acid, was isolated from the methanol extract of Tamarix aucheriana and was shown to possess proteasome inhibitory activity.
  
  
  METHODS
  Using Surflex-Dock program interfaced with SYBYL, the docking affinities of syringic acid and its proposed derivatives to 20S proteasome were studied. Several derivatives were virtually proposed, however, five derivatives: benzyl 4-hydroxy-3,5-dimethoxybenzoate (2), benzyl 4-(benzyloxy)-3,5-dimethoxybenzoate (3), 3'-methoxybenzyl 3,5-dimethoxy-4-(3'-methoxybenzyloxy)benzoate (4), 3'-methoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (5) and 3',5'-dimethoxybenzyl 4-hydroxy-3,5-dimethoxybenzoate (6), were selected based on high docking scores, synthesized, and tested for their anti-mitogenic activity against human colorectal, breast and malignant melanoma cells as well as normal human fibroblast cells.
  
  
  RESULTS
  Derivatives 2, 5, and 6 showed selective dose-dependent anti-mitogenic effect against human malignant melanoma cell lines HTB66 and HTB68 with minimal cytotoxicity on colorectal and breast cancer cells as well as normal human fibroblast cells. Derivatives 2, 5 and 6 significantly (p ≤ 0.0001) inhibited the various proteasomal chymotrypsin, PGPH, and trypsin like activities. They growth arrested the growth of HTB66 cells at G1 and G2-phases. They also arrested the growth of HTB68 cells at S- and G2-phase, respectively. Moreover, derivatives 2, 5, and 6 markedly induced apoptosis (≥ 90%) in both HTB66 and HTB68.
  
  
  CONCLUSIONS
  Computer-derived syringic acid derivatives possess selective anti-mitogenic activity on human malignant melanoma cells that may be attributed to perturbation of cell cycle, induction of apoptosis and inhibition of various 26S proteasomal activities.
authors: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Health Sciences Center, Kuwait University, Safat 13110, Kuwait. kyorabi@hsc.edu.kw.
authors: Khaled Y
authors: KY
authors: Orabi
authors: Mohamed S
authors: MS
authors: Abaza
authors: Khalid A
authors: KA
authors: El Sayed
authors: Ahmed Y
authors: AY
authors: Elnagar
authors: Rajaa
authors: R
authors: Al-Attiyah
authors: Radhika P
authors: RP
authors: Guleri
references: J Neurochem. 2001 May;77(4):1010-7
references: 11359866
references: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):3850-5
references: 10725400
references: CA Cancer J Clin. 1999 Jan-Feb;49(1):33-64, 1
references: 10200776
references: N Engl J Med. 2005 Jun 16;352(24):2487-98
references: 15958804
references: Bioorg Med Chem. 2007 Aug 1;15(15):5076-82
references: 17544279
references: Cell. 2003 Oct 3;115(1):71-82
references: 14532004
references: Antioxid Redox Signal. 2006 Jan-Feb;8(1-2):121-9
references: 16487045
references: Nat Rev Drug Discov. 2006 Jul;5(7):596-613
references: 16816840
references: Angew Chem Int Ed Engl. 2010 Dec 3;49(49):9346-67
references: 20927786
references: Anticancer Agents Med Chem. 2008 Aug;8(6):603-17
references: 18690825
references: J Agric Food Chem. 2009 Jul 22;57(14):6468-73
references: 19601677
references: J Med Chem. 2004 Jan 29;47(3):558-65
references: 14736237
references: Mol Med. 2002 Jul;8(7):382-92
references: 12393936
references: J Org Chem. 2000 Feb 25;65(4):990-5
references: 10814045
references: Int J Cancer. 2001 Oct 15;94(2):153-6
references: 11668491
references: J Biol Chem. 2001 Apr 20;276(16):13322-30
references: 11278274
references: Neurotox Res. 2006 Jan;9(1):29-37
references: 16464750
references: J Med Chem. 2008 May 8;51(9):2587-8
references: 18393400
references: Adv Exp Med Biol. 2008;615:251-60
references: 18437898
references: Breast Cancer Res. 2004;6(2):R63-74
references: 14979919
references: Cell Death Differ. 1998 Dec;5(12):1062-75
references: 9894613
references: Clin Cancer Res. 2008 Mar 15;14(6):1649-57
references: 18347166
references: Trends Pharmacol Sci. 2010 Jun;31(6):255-65
references: 20363514
references: J Mol Biol. 2001 Aug 17;311(3):543-8
references: 11493007
references: Bioorg Med Chem. 2004 Jul 1;12(13):3521-7
references: 15186836
references: Biomed Khim. 2006 Mar-Apr;52(2):138-45
references: 16805384
references: Ann N Y Acad Sci. 2006 May;1067:394-9
references: 16804017
references: J Med Chem. 2003 Jun 5;46(12):2287-303
references: 12773034
references: Curr Cancer Drug Targets. 2011 Mar;11(3):239-53
references: 21247388
references: Curr Protein Pept Sci. 2008 Jun;9(3):227-39
references: 18537678
references: Drug Resist Updat. 1999 Aug;2(4):215-223
references: 11504494
references: J Virol. 2007 Apr;81(7):3142-50
references: 17229707
references: Blood. 2008 Mar 1;111(5):2765-75
references: 18057228
references: Neoplasia. 2003 May-Jun;5(3):255-66
references: 12869308
references: Biochim Biophys Acta. 2007 Feb;1773(2):93-104
references: 17023064
references: J Clin Invest. 2008 Feb;118(2):491-504
references: 18219387
references: Front Biosci. 2005 May 01;10:1010-23
references: 15769601
references: J Clin Oncol. 2005 Feb 1;23(4):667-75
references: 15613697
references: Food Chem Toxicol. 2010 Aug-Sep;48(8-9):2508-16
references: 20600540
references: J Med Chem. 2003 Feb 13;46(4):499-511
references: 12570372
references: Blood. 2007 Nov 1;110(9):3281-90
references: 17591945
references: Crit Rev Oncol Hematol. 2006 Jun;58(3):177-89
references: 16427303
references: Int J Mol Med. 2003 Dec;12(6):879-87
references: 14612961
references: Cell. 2000 Jan 7;100(1):57-70
references: 10647931
references: Biochem Pharmacol. 2003 Sep 15;66(6):965-76
references: 12963483
references: Biol Chem. 2007 Jan;388(1):107-17
references: 17214555
references: J Biol Chem. 1999 Aug 20;274(34):23787-93
references: 10446139
references: Nature. 2003 Dec 18;426(6968):895-9
references: 14685250
references: J Allergy Clin Immunol. 2001 Oct;108(4 Suppl):S99-103
references: 11586274
references: Chem Biol. 1996 Jun;3(6):449-62
references: 8807875
references: Nat Rev Cancer. 2004 May;4(5):349-60
references: 15122206
references: Biochem Pharmacol. 2005 May 15;69(10):1421-32
references: 15857606