Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 9, Pages 2551-2559Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2013.02.033
Keywords
Cyclooxygenase; Lipoxygenase; Colon cancer; Dual COX-LOX inhibitor; Hyaluronan; CD44v6; Cell proliferation and drug resistance
Funding
- National Institutes of Health [P20RR021949, P20RR016434, P20RR16461-05, HL033756-24, 1 P30AR050953]
- Medical University of South Carolina University [2204000-24330, 2204000-24329]
- CSIR, New Delhi, India
- [1R03CA167722-01A1]
- [Mitral-07 CVD 04]
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Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) enzyme have been found to play a role in promoting growth in colon cancer cell lines. The di-tert-butyl phenol class of compounds has been found to inhibit both COX-2 and 5-LOX enzymes with proven effectiveness in arresting tumor growth. In the present study, the structural analogs of 2,6 di-tert-butyl-p-benzoquinone (BQ) appended with hydrazide side chain were found to inhibit COX-2 and 5-LOX enzymes at micromolar concentrations. Molecular docking of the compounds into COX-2 and 5-LOX protein cavities indicated strong binding interactions supporting the observed cytototoxicities. The signaling interaction between endogenous hyaluronan and CD44 has been shown to regulate COX-2 activities through ErbB2 receptor tyrosine kinase (RTK) activation. In the present studies it has been observed for the first time, that three of our COX/5-LOX dual inhibitors inhibit proliferation upon hydrazide substitution and prevent the activity of pro-angiogenic factors in HCA-7, HT-29, Apc10.1 cells as well as the hyaluronan synthase-2 (Has2) enzyme over-expressed in colon cancer cells, through inhibition of the hyaluronan/CD44v6 cell survival pathway. Since there is a substantial enhancement in the antiproliferative activities of these compounds upon hydrazide substitution, the present work opens up new opportunities for evolving novel active compounds of BQ series for inhibiting colon cancer. (C) 2013 Elsevier Ltd. All rights reserved.
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