ABSTRACT
We have designed a series of hydroxy(aryl)-λ(3)-iodane-[18]crown-6 complexes, prepared from the corresponding iodosylbenzene derivatives and superacids in the presence of [18]crown-6, and have investigated their reactivities in aqueous media. These activated iodosylbenzene monomers are all non-hygroscopic shelf-storable reagents, but they maintain high oxidizing ability in water. The complexes are effective for the oxidation of phenols, sulfides, olefins, silyl enol ethers, and alkyl(trifluoro)borates under mild conditions. Furthermore, hydroxy-λ(3)-iodane-[18]crown-6 complexes serve as efficient progenitors for the synthesis of diaryl-, vinyl-, and alkynyl-λ(3)-iodanes in water. Other less polar organic solvents, such as methanol, acetonitrile, and dichloromethane, are also usable in some cases.
Subject(s)
Crown Ethers/chemistry , Iodine/chemistry , Iodobenzenes/chemistry , Models, Molecular , Oxidation-ReductionABSTRACT
VEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signal-targeted drugs have been approved for clinical use, their utility is limited by associated toxicities or resistance to such therapy. To overcome these limitations, we developed TAS-115, a novel VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase inhibitor with an improved safety profile. TAS-115 inhibited the kinase activity of both VEGFR2 and MET and their signal-dependent cell growth as strongly as other known VEGFR or MET inhibitors. On the other hand, kinase selectivity of TAS-115 was more specific than that of sunitinib and TAS-115 produced relatively weak inhibition of growth (GI50 > 10 µmol/L) in VEGFR signal- or MET signal-independent cells. Furthermore, TAS-115 induced less damage in various normal cells than did other VEGFR inhibitors. These data suggest that TAS-115 is extremely selective and specific, at least in vitro. In in vivo studies, TAS-115 completely suppressed the progression of MET-inactivated tumor by blocking angiogenesis without toxicity when given every day for 6 weeks, even at a serum-saturating dose of TAS-115. The marked selectivity of TAS-115 for kinases and targeted cells was associated with improved tolerability and contributed to the ability to sustain treatment without dose reduction or a washout period. Furthermore, TAS-115 induced marked tumor shrinkage and prolonged survival in MET-amplified human cancer-bearing mice. These data suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved antitumor efficacy and decreased toxicity.
Subject(s)
Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Quinolines/pharmacology , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Thiourea/analogs & derivatives , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/toxicity , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Enzyme Activation/drug effects , Humans , Mice , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/metabolism , Phosphorylation/drug effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/toxicity , Quinolines/administration & dosage , Thiourea/administration & dosage , Thiourea/pharmacology , Tumor Burden/drug effects , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Xenograft Model Antitumor AssaysABSTRACT
Reported here for the first time are the synthesis, isolation, and characterization of hypervalent beta-haloalkenyl-lambda3-bromanes. Exposure of terminal alkynes to p-trifluoromethylphenyl(difluoro)-lambda3-bromane activated by BF3-i-Pr2O resulted in fluoro-lambda3-bromanation of the triple bonds in a Markovnikov fashion, yielding (E)-beta-fluoroalkenyl-lambda3-bromanes stereoselectively in good yields. 5-Chloro-1-pentynes undergo domino lambda3-bromanation-chlorine shift-fluorination or lambda3-bromanation-chlorine shift-alkyl shift-fluorination reaction, depending on the substituents and afford (E)-beta-chloroalkenyl-lambda3-bromanes stereoselectively in high yields. The beta-chloroalkenyl-lambda3-bromanes contain three kinds of halogen atoms, F, Cl, and Br, in the molecule.
ABSTRACT
[structure: see text] 4-tert-Butyl-1-cyclohexenyl(phenyl)(tetrafluoroborato)-lambda(3)-iodane forms a discrete supramolecular complex by the reaction with 18-crown-6. Solvolysis of the cyclohexenyl-lambda(3)-iodane in the presence of 18-crown-6 indicates that the complexation with 18-crown-6 tends to decrease the leaving group ability of hypervalent phenyl-lambda(3)-iodanyl groups.
ABSTRACT
Thermal decomposition of 1-tert-butylperoxy-1,2-benziodoxol-3(1H)-one in cyclic ethers and acetals at 50 degrees C generates alpha-oxy carbon-centered radicals, which undergo an addition reaction with vinyl sulfones and unsaturated esters.
Subject(s)
Acetals/chemistry , Alkenes/chemistry , Alkenes/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Carbon/chemistry , Electrons , Ethers, Cyclic/chemistry , Iodine Compounds/pharmacology , Models, Biological , Sulfones/chemistryABSTRACT
The single crystal X-ray structure of the supramolecular complex formed between diphenyl-lambda3-iodane (Ph2IBF4) or 1-alkynyl(phenyl)-lambda3-iodane [Bu(t)CCI(Ph)BF4] and 1,10-phenanthroline indicates a hitherto unknown distorted trigonal bipyramidal geometry around iodine(III), in which 1,10-phenanthroline acts as a bidentate ligand and occupies equatorial sites.
ABSTRACT
Reported here for the first time are the synthesis and characterization of supramolecular complexes between diaryl-lambda(3)-iodanes and 18-crown-6 (18C6). Slow evaporation of solvents afforded 1:1 and 2:1 complexes between Ph(2)IBF(4) and 18C6 as stable crystals, depending on the conditions. X-ray crystal structures of these complexes indicated that each iodine atom contacts with the three adjacent oxygen atoms of 18C6 through two hypervalent secondary bonding and a weak interaction. (1)H NMR analyses and CSI-MS spectra showed that, in dichloromethane solution, Ph(2)IBF(4) exclusively forms the 1:1 complex with 18C6 (binding constant K(a), 1.02 x 10(3) M(-)(1)). The binding constants decrease with the increased solvent donor ability (Gutmann's DN). Changing the heteroatom ligand from BF(4) to the less nucleophilic PF(6) and AsF(6) increased the binding constant by about six times. Substitution of an electron-withdrawing group onto the para position of Ph(2)IBF(4) tends to increase in the complex stability. A linear Hammett relationship (rho = 0.59) between log K(a) and sigma(p)(+) values of substituents indicates that the diaryl-lambda(3)-iodanes with electropositive iodine(III) interact more efficiently with 18C6. Decreased binding magnitude was measured with 15C5, dibenzo-18C6, dibenzo-21C7, and dibenzo-30C10.
