Novel Esters and Amides of Nonsteroidal Antiinflammatory Carboxylic Acids as Antioxidants and Antiproliferative Agents

• Published in: Journal of medicinal chemistry Vol. 42; no. 2; pp. 267 - 276
• Main Authors: Hellberg, Mark R, Namil, Abdelmoula, Delgado, Pete, David, Karen C, Kessler, Timothy L, Graff, Gustav, Haggard, Karen S, Nixon, Jon C
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.01.1999; Amer Chemical Soc
• Subjects: Amides; Animals; Anti-Inflammatory Agents, Non-Steroidal - chemistry; Antineoplastic agents; Antioxidants - chemistry; Antioxidants - pharmacology; Biological and medical sciences; Carboxylic Acids - chemistry; Cattle; Cell Division - drug effects; Cells, Cultured; Chemistry, Medicinal; Child, Preschool; DNA - drug effects; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Esters; Female; General aspects; Humans; Life Sciences & Biomedicine; Lipid Peroxidation - drug effects; Magnetic Resonance Spectroscopy; Medical sciences; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; DIABETIC-RETINOPATHY; PROTEIN-KINASE-C; VITAMIN-E; ALPHA-TOCOPHEROL; IRIS NEOVASCULARIZATION; MACULAR DEGENERATION; INHIBITS PROLIFERATION; VITREOUS SURGERY; ENDOTHELIAL GROWTH-FACTOR; MUSCLE CELL-PROLIFERATION; Antineoplastic agent; Human; Cell proliferation; Endothelial cell; DNA synthesis; Antioxidant; Oxygen heterocycle; In vitro; Naphthalene derivatives; Chroman derivatives; Cell line; Structure activity relation; Naproxen; Blood vessel; Phenols; Arylpropionic acid derivatives; Carboxamide; Aromatic compound; Benzofuran derivatives; Inhibition; Chemical synthesis; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm980430o

A series of phenolic antioxidant ester and amide derivatives of the nonsteroidal antiinflammatory drug naproxen was designed to have both antiinflammatory and cytoprotective activity. Compounds were evaluated in vitro both for antioxidant activity, as assessed indirectly by thiobarbituric acid reactive substance (TBARS) formation in a membrane lipid peroxidation assay, and for antiproliferative activity, as indexed by the inhibition of DNA synthesis in cultured human vascular endothelial cells. Compounds of this series exhibited potent antioxidant activity, with IC50 values (1.6−11.63 μM) 2−6-fold lower than that of Trolox (6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid) and 400−1300-fold lower than that of vitamin E. Structural modifications of the ester or amide substructure (5a and 6a) did not affect antioxidant activity, but methylation of the 6-hydroxy substituent resulted in compound 6f which was devoid of antioxidant activity. Although indistinguishable in antioxidant activity, the amide derivatives tended to be more potent as antiproliferative agents than the corresponding esters. The IC50's for the amide derivatives (3, 5a − e, 8) ranged from 2 to 7 μM, while the IC50's for the structurally related esters (1, 2a − c, 6a − e) ranged from 9 to 22 μM. Moreover, studies with compound 6a indicate that the observed inhibition of DNA synthesis is reversible, suggesting that the antiproliferative activity is due to a cytostatic rather than cytotoxic activity of the compounds. Thus, the antioxidant−naproxen derivatives represent a novel series of agents that both protect against free-radical damage and possess cytostatic activity in vascular endothelial cells. Studies are in progress to assess the utility of these compounds as potential components of an ocular irrigating solution.