Azetidine synthesis by La(OTf)3-catalyzed intramolecular regioselective aminolysis of cis-3,4-epoxy amines

Azetidine is a prevalent structural motif found in various biologically active compounds. In this research paper, we report La(OTf)3-catalyzed intramolecular regioselective aminolysis of cis-3,4-epoxy amines to afford azetidines. This reaction proceeded in high yields even in the presence of acid-sensitive and Lewis basic functional groups

Identification of anti-cancer chemical compounds using Xenopus embryos

Cancer tissues have biological characteristics similar to those observed in embryos during development. Many types of cancer cells acquire pro-invasive ability through epithelial-mesenchymal transition (EMT). Similar processes (gastrulation and migration of cranial neural crest cells [CNCC]) are observed in the early stages of embryonic development in Xenopus during which cells that originate from epithelial sheets through EMT migrate to their final destinations. The present study examined Xenopus embryonic tissues to identify anti-cancer compounds that prevent cancer invasion. From the initial test of known anti-cancer drugs, AMD3100 (an inhibitor of CXCR4) and paclitaxel (a cytoskeletal drug targeting microtubules) effectively prevented migration during gastrulation or CNCC development. Blind-screening of 100 synthesized chemical compounds was performed, and nine candidates that inhibited migration of these embryonic tissues without embryonic lethality were selected. Of these, C-157 (an analog of podophyllotoxin) and D-572 (which is an indole alkaroid) prevented cancer cell invasion through disruption of interphase microtubules. In addition, these compounds affected progression of mitotic phase and induced apoptosis of SAS oral cancer cells. SAS tumors were reduced in size after intratumoral injection of C-157, and peritoneal dissemination of melanoma cells and intracranial invasion of glioma cells were inhibited by C-157 and D-572. When the other analogues of these chemicals were compared, those with subtle effect on embryos were not tumor suppressive. These results suggest that a novel chemical-screening approach based on Xenopus embryos is an effective method for isolating anti-cancer drugs and, in particular, targeting cancer cell invasion and proliferation

The Synthetic Curcumin Analogue GO-Y030 Effectively Suppresses the Development of Pressure Overload-induced Heart Failure in Mice

Curcumin is a naturally occurring p300-histone acetyltransferase (p300-HAT) inhibitor that suppresses cardiomyocyte hypertrophy and the development of heart failure in experimental animal models. To enhance the therapeutic potential of curcumin against heart failure, we produced a series of synthetic curcumin analogues and investigated their inhibitory activity against p300-HAT. The compound with the strongest activity was further evaluated to determine its effects on cardiomyocyte hypertrophy and pressure overload-induced heart failure in mice. We synthesised five synthetic curcumin analogues and found that a compound we have named GO-Y030 most strongly inhibited p300-HAT activity. Furthermore, 1 μM GO-Y030, in a manner equivalent to 10 µM curcumin, suppressed phenylephrine-induced hypertrophic responses in cultured cardiomyocytes. In mice undergoing transverse aortic constriction surgery, administration of GO-Y030 at a mere 1% of an equivalently-effective dose of curcumin significantly attenuated cardiac hypertrophy and systolic dysfunction. In addition, this low dose of GO-Y030 almost completely blocked histone H3K9 acetylation and eliminated left ventricular fibrosis. A low dose of the synthetic curcumin analogue GO-Y030 effectively inhibits p300-HAT activity and markedly suppresses the development of heart failure in mice

Curcumin analog, GO-Y078, overcomes resistance to tumor angiogenesis inhibitors

Tumor angiogenesis inhibition is one of the most potent strategies in cancer chemotherapy. From past clinical studies, inhibition of the vascular endothelial growth factor pathway successfully treats malignant tumors. However, vascular endothelial growth factor inhibitors alone cannot cure tumors. Moreover, resistance to small molecule inhibitors has also been reported. Herein, we show the antiangiogenic potential of a newly synthesized curcumin analog, GO-Y078, that possibly functions through inhibition of actin stress fiber formation, resulting in mobility inhibition; this mechanism is different from that of vascular endothelial growth factor inhibition. In addition, we examined the detailed mechanism of action of the antiangiogenesis potential of GO-Y078 using human umbilical venous epithelial cells resistant to angiogenesis inhibitors (HUVEC-R). GO-Y078 inhibited the growth and mobility of HUVEC-R at 0.75mol/L concentration. Expression analyses by microarray and RT-PCR showed that expressions of genes including that of fibronectin 1 were significantly suppressed. Among these genes, fibronectin 1 is abundantly expressed and, therefore, seems to be a good target for GO-Y078. In a knockdown experiment using Si-oligo of fibronectin 1 (FN1), FN1 expression was decreased to half of that in mock experiments as well as GO-Y078. Knockdown of FN1 resulted in the suppression of HUVEC-R growth at 24hours after treatment. Fibronectin is a key molecule contributing to angiogenesis that could be inhibited by GO-Y078. Thus, resistance to vascular endothelial growth factor inhibition can be overcome using GO-Y078

The Synthetic Curcumin Analogue GO-Y030 Effectively Suppresses the Development of Pressure Overload-induced Heart Failure in Mice

Curcumin is a naturally occurring p300-histone acetyltransferase (p300-HAT) inhibitor that suppresses cardiomyocyte hypertrophy and the development of heart failure in experimental animal models. To enhance the therapeutic potential of curcumin against heart failure, we produced a series of synthetic curcumin analogues and investigated their inhibitory activity against p300-HAT. The compound with the strongest activity was further evaluated to determine its effects on cardiomyocyte hypertrophy and pressure overload-induced heart failure in mice. We synthesised five synthetic curcumin analogues and found that a compound we have named GO-Y030 most strongly inhibited p300-HAT activity. Furthermore, 1 μM GO-Y030, in a manner equivalent to 10 µM curcumin, suppressed phenylephrine-induced hypertrophic responses in cultured cardiomyocytes. In mice undergoing transverse aortic constriction surgery, administration of GO-Y030 at a mere 1% of an equivalently-effective dose of curcumin significantly attenuated cardiac hypertrophy and systolic dysfunction. In addition, this low dose of GO-Y030 almost completely blocked histone H3K9 acetylation and eliminated left ventricular fibrosis. A low dose of the synthetic curcumin analogue GO-Y030 effectively inhibits p300-HAT activity and markedly suppresses the development of heart failure in mice

C–H Alkylation of Cubanes via Polar Effect-Assisted Photocatalytic Generation of Cubyl Radicals

A method for C–H alkylation of cubanes is described herein. A hydrogen atom–transfer catalyst enables direct abstraction of a hydrogen atom from the C–H bond of cubanes, followed by conjugate addition of the generated cubyl radicals to various Michael acceptors. Synthetic applications of the developed functionalization method are also described

Concise Entry to Chiral 5‑(4-Hydroxybutyl)-2(5<i>H</i>)‑furanone via HTIB-Mediated Novel Oxidative Fragmentation: Formal Total Synthesis of (+)-Dubiusamine A

The concise synthesis of 5-(4-hydroxybutyl)-2(5<i>H</i>)furanone has been accomplished from 9-oxabicyclo[4.2.1]non-7-en-1-ol on the basis of HTIB [PhI(OH)OTs, a.k.a. Koser’s reagent]-mediated novel oxidative fragmentation. Chiral (−)-(<i>R</i>)-5-(4-hydroxy-butyl)-2(5<i>H</i>)-furanone (>99% ee) was used for the formal total synthesis of (+)-dubiusamine A (<b>1</b>)