title: Photoinduced Isomerization and Hepatoxicities of Semaxanib, Sunitinib and Related 3-Substituted Indolin-2-ones.
abstract: 3-Substituted indolin-2-ones are an important class of compounds that display a wide range of biological activities. Sunitinib is an orally available multiple tyrosine kinase inhibitor that has been approved by the US Food and Drug Administration (FDA) for the treatment of renal cell cancer. Sunitinib and a related compound, semaxanib, exist as thermodynamically stable Z isomers, which photoisomerize to E isomers in solution. In this study, 17 3-substituted indolin-2-ones were synthesized, and the kinetics of their photoisomerization were studied by (1)H NMR spectroscopy. The rate constants for photoisomerization ranged from 0.009 to 0.048 h(-1). Selected compounds were tested for cytotoxicity in the TAMH liver cell line. E/Z mixtures of four compounds were also assessed for toxicity in the TAMH and HepG2 cell lines. In some cases, the stereochemically pure drug was more toxic than the E/Z mixtures, but a general statement cannot be made. Our studies show that each stereoisomer could contribute differently to toxicity, suggesting that stereochemical purity issues that could arise from isomerization cannot be ignored.
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Mun Hong
authors.initials: MH
authors.lastname: Ngai
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Choon Leng
authors.initials: CL
authors.lastname: So
authors.affiliation: Institute of High-Performance Computing, Agency for Science Technology and Research, Singapore, 1 Fusionopolis Way, #16-16 Connexis, Singapore, 138632, Singapore.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Sullivan
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Han Kiat
authors.initials: HK
authors.lastname: Ho
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore. phacllc@nus.edu.sg.
authors.forename: Christina L L
authors.initials: CL
authors.lastname: Chai
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D015394:Molecular Structure; D055668:Photochemical Processes; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000077210:Sunitinib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C456900:indolin-2-one; C116890:Semaxinib; D011505:Protein-Tyrosine Kinases; D000077210:Sunitinib
keywords: computational chemistry; cytotoxicity; indolin-2-ones; kinetics; photoisomerization