title: Synthesis and Biological Evaluation of NovelN-phenyl-5-carboxamidyl Isoxazoles as Potential Chemotherapeutic Agents for Colon Cancer.
abstract: A new series of isoxazole derivatives,N-phenyl-5-carboxamidyl isoxazoles, was investigated for their anticancer activity with solid tumor selectivity. SixN-phenyl-5-carboxamidylisoxazoles were chemically synthesized and evaluated by thein vitrodisk-diffusion assay and IC50cytotoxicity determination. The results showed that one of the derivatives, compound3,N-(4-chlorophenyl)-5-carboxamidyl isoxazole, was the most active against colon 38 and CT-26 mouse colon tumor cells with an IC50of 2.5 μg/mL for both cell lines. Western blot analysis showed that compound3significantly down-regulated the expression of phosphorylated STAT3 in both human and mouse colon cancer cells indicating that the mechanism of action for compound3may involve the inhibition of JAK3/STAT3 signaling pathways. Flow cytometric analysis with Annexin V staining showed that the death induced by compound3is mediated through cell necrosis and not apoptotic pathway. In summary, our results show that compound3is a newN-phenyl-5-carboxamidyl isoxazole with potential anticancer activity. Compound3inhibits the phosphorylation of STAT3, a novel target for chemotherapeutic drugs, and is worthy of further investigation as a potential chemotherapeutic agent for treating colon cancer.
authors.affiliation: 21 Century Therapeutics, Inc., Ferndale, MI 48220, USA.
authors.forename: Jiajiu
authors.initials: J
authors.lastname: Shaw
authors.affiliation: Department of Internal Medicine, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Ben
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, Michigan 48202, USA.
authors.forename: Jean P
authors.initials: JP
authors.lastname: Bourgault
authors.affiliation: Department of Neurology, Henry Ford Hospital, Detroit, Michigan 48202, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Department of Pharmaceutical Sciences, ILR College of Pharmacy, Texas A&M University System Health Science Center, Kingsville, Texas 78363, USA.
authors.forename: Narendra
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutical Sciences, ILR College of Pharmacy, Texas A&M University System Health Science Center, Kingsville, Texas 78363, USA.
authors.forename: Jayshree
authors.initials: J
authors.lastname: Mishra
authors.affiliation: Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Valeriote
authors.affiliation: Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA.
authors.forename: Joe
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authors.lastname: Media
authors.affiliation: Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan 48202, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bobbitt
authors.affiliation: Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA.
authors.forename: Halina
authors.initials: H
authors.lastname: Pietraszkiewicz
authors.affiliation: Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan 48202, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Edelstein
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, Michigan 48202, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Andreana