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A convenient one-flask synthesis of α-methylenealdehydes from primary alcohols has been established.

A novel series of trans-N-aryl-2,5-dimethylpiperazine-1-carboxamide derivatives was synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic effects were evaluated. Pharmacological assays indicated that compound 33 was a potent AR antagonist, and subsequent optical resolution provided (+)-(2R,5S)-4-[4-cyano-3-(trifluoromethyl)phenyl]-2,5-dimethyl-N-[6-(trifluoromethyl)pyridin-3-yl]piperazine-1-carboxamide (33a, YM580) which exhibited the most potent antiandrogenic activity. Unlike bicalutamide, compound 33a decreased the weight of rat ventral prostate in a dose-dependent manner (ED(50) = 2.2 mg/kg/day), and induced the maximum antiandrogenic effect, comparable to that of surgical castration, without significantly affecting serum testosterone levels. Compound 33a is a promising clinical candidate for prostate cancer monotherapy.

Purpose: The vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase has been implicated in the pathologic angiogenesis associated with tumor growth. YM-359445 was a (3Z)-3-quinolin-2(1H)-ylidene-1,3-dihydro-2H-indol-2-one derivative found while screening based on the inhibition of VEGFR2 tyrosine kinase.The aim of this study was to analyze the efficacy of this compound both in vitro and in vivo. Experimental Design:We tested the effects ofYM-359445 onVEGFR2 tyrosine kinase activity, cell proliferation, and angiogenesis. The antitumor activity of YM-359445 was also tested in nude mice bearing various established tumors and compared with other VEGFR2 tyrosine kinase inhibitors (ZD6474, CP-547632, CGP79787, SU11248, and AZD2171), a cytotoxic agent (paclitaxel), and an epidermal growth factor receptor tyrosine kinase inhibitor (gefitinib). Results: The IC 50 of YM-359445 for VEGFR2 tyrosine kinase was 0.0085 Amol/L. In human vascular endothelial cells, the compound inhibited VEGF-dependent proliferation, VEGFR2 autophosphorylation, and sprout formation at concentrations of 0.001 to 0.003 Amol/L. These concentrations had no direct cytotoxic effect on cancer cells. In mice bearing various established tumors, including paclitaxel-resistant tumors, once daily oral administration of YM-359445 at doses of 0.5 to 4 mg/kg not only inhibited tumor growth but also reduced its vasculature. YM-359445 had greater antitumor activity than other VEGFR2 tyrosine kinase inhibitors. Moreover, in human lung cancer A549 xenografts, YM-359445 markedly regressed the tumors (73%) at a dose of 4 mg/kg, whereas gefitinib caused no regression even at 100 mg/kg. Conclusion: Our results show that YM-359445 is more potent than orally bioavailable VEGFR2 tyrosine kinase inhibitors, which leads to great expectations for clinical applicability.Morbidity rate of cancer has been increasing remarkably in recent decades, and the development of diagnostic rapid capabilities has supported early detection and treatment. Although chemotherapy using anticancer drugs began >50 years ago, and the number of anticancer drugs has increased considerably, the prognosis of most patients has not yet been improved because of serious side effects or multidrug resistance (1). As a means of overcoming these problems, antiangiogenesis therapy targeting the vascular endothelial cells in tumors has attracted attention. This is because endothelial cells rarely acquire resistance due to their genetic stability, but cancer cells easily acquire resistance during chemotherapy through the use of cytotoxic agents (2, 3).Angiogenesis is the complex process of forming new blood vessels from the preexisting vessels that occurs due to many physiologic and pathologic conditions (4, 5). The protrusion of endothelial cells allows local degradation of the basement membrane of the parent vessel; then, endothelial cells migrate outward in tandem to form a capillary sprout. The cells then proliferate followed by lumen formation with subsequent branching; however, th...