Structural studies on bioactive compounds. 32. Oxidation of tryphostin 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 produc ts depending on the structure of the phenolic substrate, the solvent, the o xidant stoichiometry, and the purification strategy. Conditions have been d eveloped to modify the phenolic component of the tyrphostin without affecti ng the appended substituted-vinyl moiety. Novel products include: unstable 2-acyloxy-2-methoxy-4-(substituted-vinyl)cyclohexadienones and their rearra ngement products 2-acyloxy-4-hydroxy-3 -methoxy-1-(substituted-vinyl)benzen es; phenyliodoniophenolates and their rearrangement products iodophenoxytyr phostins; and 3,3'-dialkoxy-2,2'-dihydroxy-5,5'-di(substituted-vinyl)biphen yls. 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 lin es, compared to their tyrphostin precursors. The inhibitory activity of thr ee representative tyrphostins (3e,n, 28) was not modulated by aerobic/anaer obic conditions in MCF-7 and MDA 468 cells and was independent of EGFR stat us 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 autaphosphorylation in cell lysates from MDA 468 or SkBr3 cells, re spectively, suggesting that receptor tyrosine kinases are not targets for t hese compounds. Growth stimulation by the tyrphostin 3n in the ER+ breast c ell lines MCF-7, T47D, and ZR75-1 was abolished by 1 mu M tamoxifen, sugges ting that this compound has estrogen agonist activity.