Novel non-cyclooxygenase inhibitory derivatives of naproxen for colorectal cancer chemoprevention.

Autor: Aboul-Fadl T; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia., Al-Hamad SS; Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia., Lee K; Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Li N; Department of Biochemistry, The University of Alabama at Birmingham, Birmingham, AL 35205, USA., Gary BD; Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Keeton AB; Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Piazza GA; Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA., Abdel-Hamid MK; Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
Jazyk: angličtina
Zdroj: Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents [Med Chem Res] 2014 Sep; Vol. 23 (9), pp. 4177-4188.
DOI: 10.1007/s00044-014-0979-z
Abstrakt: A structure-based medicinal chemistry strategy was applied to design new naproxen derivatives that show growth inhibitory activity against human colon tumor cells through a cyclooxygenase (COX)-independent mechanism. In vitro testing of the synthesized compounds against the human HT-29 colon tumor cell line revealed enhanced growth inhibitory activity compared to the parent naproxen with 3a showing IC 50 of 11.4 μM (two orders of magnitude more potent than naproxen). Selectivity of 3a was investigated against a panel of three tumor and one normal colon cell lines and showed up to six times less toxicity against normal colonocytes. Compound 3a was shown to induce dose-dependent apoptosis of HT116 colon tumor cells as evidenced by measuring the activity of caspases-3 and 7. None of the synthesized compounds showed activity against COX-1 or COX-2 isozymes, confirming a COX-independent mechanism of action. Compound 3k was found to have no ulcerogenic effect in rats as indicated by electron microscope scanning of the stomach after oral administration. A pharmacophore model was developed for elucidating structure-activity relationships and subsequent chemical optimization for this series of compounds as colorectal cancer chemopreventive drugs.
Databáze: MEDLINE
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