Structural studies on bioactive compounds. 32. Oxidation of tyrphostin protein tyrosine kinase inhibitors with hypervalent iodine reagents.
Hydroxylated styrenes (tyrphostins) undergo oxidation by hypervalent iodine oxidants such as [(diacetoxy)iodo]benzene (DAIB) to give a range of products depending on the structure of the phenolic substrate, the solvent, the oxidant stoichiometry, and the purification strategy. Conditions have been developed to modify the phenolic component of the tyrphostin without affecting the appended substituted-vinyl moiety. Novel products include: unstable 2-acyloxy-2-methoxy-4-(substituted-vinyl)cyclohexadienones and their rearrangement products 2-acyloxy-4-hydroxy-3-methoxy-1-(substituted-vinyl)benzenes; phenyliodoniophenolates and their rearrangement products iodophenoxytyrphostins; and 3,3'-dialkoxy-2,2'-dihydroxy-5, 5'-di(substituted-vinyl)biphenyls. None of these oxidation products displayed enhanced activity in vitro in the NCI 60-cell line panel or in a panel of human breast cancer cell lines, compared to their tyrphostin precursors. The inhibitory activity of three representative tyrphostins (3e,n, 28) was not modulated by aerobic/anaerobic conditions in MCF-7 and MDA 468 cells and was independent of EGFR status in clones of ZR75B cells transfected with this receptor. Basal growth of MCF-7 cells was unaffected by co-administration of the growth factors EGF, TGF-alpha, IGF-I, and IGF-II, and the new agents did not inhibit EGFR and c-erbB2 autophosphorylation in cell lysates from MDA 468 or SkBr3 cells, respectively, suggesting that receptor tyrosine kinases are not targets for these compounds. Growth stimulation by the tyrphostin 3n in the ER(+) breast cell lines MCF-7, T47D, and ZR75-1 was abolished by 1 microM tamoxifen, suggesting that this compound has estrogen agonist activity.
Wells
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G
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, Nottingham NG7 2RD, U.K.
Seaton
A
A
Stevens
M F
MF
D000085:Acetates / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D004967:Estrogens / Q000819:agonists; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D007462:Iodobenzenes / Q000737:chemistry*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000737:chemistry* / Q000494:pharmacology
D000085:Acetates; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D004967:Estrogens; D006133:Growth Substances; D007202:Indicators and Reagents; D007462:Iodobenzenes; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; C008857:phenyliodosodiacetate; C407568:(bis(trifluoroacetoxy)iodo)benzene