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Hypoxia-inducible factor 1 (HIF-1) activates the transcription of genes that play crucial roles in the adaptation of cancer cells to hypoxia. HIF-1α overexpression has been associated with poor prognosis in patients with various types of cancer. Here, we describe ER-400583-00 as a novel HIF-1 inhibitor. ER-400583-00 suppressed the production of HIF-1α protein in response to hypoxia, with a half-maximal inhibitory concentration value of 3.7 nM in human U251 glioma cells. The oral administration of 100 mg/kg ER-400583-00 to mice bearing U251 tumor xenografts resulted in a rapid suppression of HIF-1α that persisted for 24 h. Immunohistochemical analysis revealed that ER-400583-00 suppressed the proliferation of cancer cells most prominently in areas distal to the region of blood perfusion, where HIF-1α-expressing hypoxic cancer cells were located. These hypoxic cancer cells were resistant to radiation therapy. ER-400583-00 showed a synergistic interaction with radiation therapy in terms of antitumor activity. These data suggest that HIF-1 blockade by small compounds may have therapeutic value in cancer, especially in combination with radiation therapy.

A novel and efficient glycosyl donor having a p-trifluoromethylbenzylthio-N-p-trifluoromethylphenylformimidate group at an anomeric position is easily prepared by the addition of anomeric hydroxy group of 2,3,4,6-tetra-O-benzyl-α,β-D-glucopyranose to p-trifluoromethylphenyl isothiocyanate, followed by treatment with p-trifluoromethylbenzyl bromide. Catalytic and stereoselective glycosylation of various glycosyl acceptors with the above glycosyl donor smoothly proceeds by using various protic and Lewis acid catalysts which interact with its nitrogen atom. Further, catalytic and highly 1,2-cis or 1,2-trans stereoselective and chemoselective glycosylation between two different “armed” and “disarmed” glycosyl p-trifluoromethylbenzylthio-N-p-trifluoromethylphenylformimidates is also performed effectively in the presence of a catalytic amount of trifluoromethanesulfonic acid (TfOH) at −78 °C in tBuOMe or EtCN, respectively. These glycosylations are applied to successful one-pot sequential syntheses of trisaccha...

Reduction of dithioacetals derived from aromatic aldehydes with low valent titanium iodide species in situ formed by treatment of titanium(IV) iodide with zinc in a mixed solvent of dichloro-methane and pivalonitrile at room temperature afforded coupling products, vicinal bis(alkylthio) derivatives, in good to high yields.

A novel and efficient glycosyl donor having a p-trifluoro-methylbenzylthio-p-trifluoromethylphenyl formimidate function as a leaving group is easily prepared by the addition of anomeric hydroxyl group of 2,3,4,6-tetra-O-benzoyl-α,β-D-glucopyranose to p-trifluoromethylphenyl isothiocyanate, followed by treatment with p-trifluoromethylbenzyl bromide. Catalytic and stereoselective glycosylation using this glycosyl donor effectively proceeds by activating its nitorogen atom with various protic and Lewis acids.

Catalytic and chemoselective glycosylation between novel “armed” and “disarmed” glycosyl p-trifluoromethylbenzylthio-p-trifluoromethylphenyl formimidates was effectively performed in the presence o...

c-Met is the cellular receptor for hepatocyte growth factor (HGF) and is known to be dysregulated in various types of human cancers. Activation of the HGF/c-Met pathway causes tumor progression, invasion, and metastasis. Vascular endothelial growth factor (VEGF) is also known as a key molecule in tumor progression through the induction of tumor angiogenesis. Because of their key roles in tumor progression, these pathways provide attractive targets for therapeutic intervention. We have generated a novel, orally active, small molecule compound, E7050, which inhibits both c-Met and vascular endothelial growth factor receptor (VEGFR)-2. In vitro studies indicate that E7050 potently inhibits phosphorylation of both c-Met and VEGFR-2. E7050 also potently represses the growth of both c-met amplified tumor cells and endothelial cells stimulated with either HGF or VEGF. In vivo studies using E7050 showed inhibition of the phosphorylation of c-Met and VEGFR-2 in tumors, and strong inhibition of tumor growth and tumor angiogenesis in xenograft models. Treatment of some tumor lines containing c-met amplifications with high doses of E7050 (50-200 mg/kg) induced tumor regression and disappearance. In a peritoneal dissemination model, E7050 showed an antitumor effect against peritoneal tumors as well as a significant prolongation of lifespan in treated mice. Our results indicate that E7050 is a potent inhibitor of c-Met and VEGFR-2 and has therapeutic potential for the treatment of cancer.

The use of pyridine-3-sulfonyl chloride (3-PSC) in dehydrating condensation was investigated. This novel reagent was successfully employed as a mild dehydrating reagent for preparing various carbox...

A highly useful method for the preparation of carboxylic esters and carboxamides from various carboxylic acids was established by using a novel condensing reagent, pyridine-3-carboxylic anhydride (...

A highly efficient method by using benzenesulfonic anhydride (BSA) in the presence of 4-(dimethylamino)pyridine (DMAP) to synthesize carboxamides from various carboxylic acids and amines including ...

A highly useful method for the preparation of carboxamides from various carboxylic acids and amines is established by using pyridine-3-carboxylic anhydride (3-PCA) in the presence of 4-(dimethylami...

A synthesis of carboxylic esters from various carboxylic acids and alcohols is successfully carried out by using a condensation reagent, pyridine-3-carboxylic anhydride (3-PCA). This reaction mater...