title: Novel non-cyclooxygenase inhibitory derivatives of naproxen for colorectal cancer chemoprevention.
abstract: 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 with3ashowing IC50of 11.4 μM (two orders of magnitude more potent than naproxen). Selectivity of3awas investigated against a panel of three tumor and one normal colon cell lines and showed up to six times less toxicity against normal colonocytes. Compound3awas 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. Compound3kwas 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.
authors: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
authors: Tarek
authors: T
authors: Aboul-Fadl
authors: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
authors: Suliman S
authors: SS
authors: Al-Hamad
authors: Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors: Kevin
authors: K
authors: Lee
authors: Department of Biochemistry, The University of Alabama at Birmingham, Birmingham, AL 35205, USA.
authors: Nan
authors: N
authors: Li
authors: Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors: Bernard D
authors: BD
authors: Gary
authors: Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors: Adam B
authors: AB
authors: Keeton
authors: Drug Discovery Research Center, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
authors: Gary A
authors: GA
authors: Piazza
authors: Department of Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
authors: Mohammed K
authors: MK
authors: Abdel-Hamid
keywords: Apoptosis; Chemoprevention; Colorectal cancer; Cyclooxygenase; NSAIDs; Naproxen; Pharmcophore; Ulcerogenicity