title: Structure-toxicity relationship and structure-activity relationship study of 2-phenylaminophenylacetic acid derived compounds.
abstract: 2-Phenylaminophenylacetic acid is a widely-exploited chemical scaffold whereby notable NSAIDs such as diclofenac and lumiracoxib were derived. Yet, their clinical usage has been associated with toxicities in the liver. While some studies have attributed toxicities to the bioactivation of both drugs to reactive intermediates, the structural predisposition for toxicity, as well as relationship between this toxicity and COX inhibitory activity has not been elucidated. In this study, we aimed to address their intricate link by synthesizing compounds that possess the 2-phenylaminophenylacetic acid backbone with varying alkyl and halogen substituents at three positions critical to the COX inhibitory pharmacophore. These compounds were subjected to cytotoxicity testing on two liver cell lines of contrasting metabolic competencies. We observed higher toxicity in the more metabolically competent cell line, supporting the role of bioactivation as a prerequisite for toxicity. We have also shown that structural changes on the chemical scaffold exerted pronounced effect on liver cytotoxicity. The most lipophilic and brominated compound (24) was identified as the most cytotoxic of all the compounds. A concurrent determination of their pharmacological activity using COX inhibition assays allowed us to derive a safety profile, which showed that selectivity towards COX-2 negatively affected activity and toxicity.
authors: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
authors: Yi Yun
authors: YY
authors: Pang
authors: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
authors: Wee Kiang
authors: WK
authors: Yeo
authors: National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore.
authors: Kep Yong
authors: KY
authors: Loh
authors: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
authors: Mei Lin
authors: ML
authors: Go
authors: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. Electronic address: phahohk@nus.edu.sg.
authors: Han Kiat
authors: HK
authors: Ho
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000633:toxicity; D051379:Mice; D013329:Structure-Activity Relationship; D018675:Toxicity Tests
chemical_list: D000814:Aniline Compounds; D005998:Glycine
keywords: Diclofenac; Liver; Lumiracoxib; Structure–activity-relationship; Structure–toxicity relationship