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Kawahara T.,Japan Biological Informatics Consortium JBiC | Izumikawa M.,Japan Biological Informatics Consortium JBiC | Takagi M.,Japan Biological Informatics Consortium JBiC | Shin-Ya K.,Japan National Institute of Advanced Industrial Science and Technology
Organic Letters | Year: 2012

JBIR-129 was isolated as the potent cytotoxic compound, which consists of the 34-membered polyol macrolide skeleton with five sugar moieties. The relative configuration of the aglycone moiety (C7-C27 and C33-C39) was established by the J-based configuration analysis using vicinal 1H-1H (from 1H NMR and PS-DQF-COSY spectra) and long-range 1H-13C coupling constants (from sge-HETLOC and several J-resolved HMBC spectra) with steric information obtained from ROESY. © 2012 American Chemical Society. Source


Fuse S.,Tokyo Institute of Technology | Okada K.,Tokyo Institute of Technology | Iijima Y.,Tokyo Institute of Technology | Munakata A.,Japan Biological Informatics Consortium JBiC | And 5 more authors.
Organic and Biomolecular Chemistry | Year: 2011

The total synthesis of a natural product HDAC inhibitor, spiruchostatin B, was successfully achieved. A 5-step synthesis that included an asymmetric aldol reaction was carried out in an automated synthesizer to provide an (E)-(S)-3-hydroxy-7-thio-4-heptenoic acid segment that is the crucial structure of cysteine-containing, depsipeptidic natural products such as spiruchostatins, FK228, FR901375, and largazole for their inhibitory activity against HDACs. © 2011 The Royal Society of Chemistry. Source


Doi T.,Tohoku University | Shibata K.,Tokyo Institute of Technology | Yoshida M.,Tohoku University | Takagi M.,Japan Biological Informatics Consortium JBiC | And 4 more authors.
Organic and Biomolecular Chemistry | Year: 2011

Total synthesis of the (S)-stereoisomer of telomestatin (1) was accomplished. (S)-Telomestatin exhibited potency four times that of the natural product, (R)-telomestatin, which was the most potent telomerase inhibitor previously reported. In the circular dichroism spectral analysis of the complexes possessing randomly structured single-stranded d[TTAGGG]4 oligonucleotide, (S)-telomestatin, like (R)-telomestatin, induced an antiparallel G-quadruplex structure. The melting temperature (Tm) value of the (S)-isomer complex was greater than that of the (R)-telomestatin complex. Therefore, it is concluded that the stereochemistry of the thiazoline of telomestatin is important to the binding ability of a G-quadruplex binder, and (S)-telomestatin as a G-quadruplex binder is more potent than the natural product. © 2011 The Royal Society of Chemistry. Source


Muraoka N.,Keio University | Yamakawa H.,Keio University | Miyamoto K.,Keio University | Sadahiro T.,Keio University | And 19 more authors.
EMBO Journal | Year: 2014

Fibroblasts can be directly reprogrammed into cardiomyocyte-like cells (iCMs) by overexpression of cardiac transcription factors or microRNAs. However, induction of functional cardiomyocytes is inefficient, and molecular mechanisms of direct reprogramming remain undefined. Here, we demonstrate that addition of miR-133a (miR-133) to Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Mesp1 and Myocd improved cardiac reprogramming from mouse or human fibroblasts by directly repressing Snai1, a master regulator of epithelial-to-mesenchymal transition. MiR-133 overexpression with GMT generated sevenfold more beating iCMs from mouse embryonic fibroblasts and shortened the duration to induce beating cells from 30 to 10 days, compared to GMT alone. Snai1 knockdown suppressed fibroblast genes, upregulated cardiac gene expression, and induced more contracting iCMs with GMT transduction, recapitulating the effects of miR-133 overexpression. In contrast, overexpression of Snai1 in GMT/miR-133-transduced cells maintained fibroblast signatures and inhibited generation of beating iCMs. MiR-133-mediated Snai1 repression was also critical for cardiac reprogramming in adult mouse and human cardiac fibroblasts. Thus, silencing fibroblast signatures, mediated by miR-133/Snai1, is a key molecular roadblock during cardiac reprogramming. Source


Kawahara T.,Japan Biological Informatics Consortium JBiC | Hwang J.-H.,Japan Biological Informatics Consortium JBiC | Izumikawa M.,Japan Biological Informatics Consortium JBiC | Hashimoto J.,Japan Biological Informatics Consortium JBiC | And 2 more authors.
Journal of Natural Products | Year: 2012

New 34-membered polyol macrolides JBIR-129 (1) and JBIR-139 (2) were isolated from the culture of the terrestrial Streptomyces RK74. The planar structures of 1 and 2 were established on the basis of 1D and 2D NMR, ESI-TOF-MS, IR, and UV spectra. The relative configurations of the sugar units were determined by analyzing vicinal 1H-1H coupling constants and steric information. Both 1 and 2 showed cytotoxic activity against human ovarian adenocarcinoma SKOV-3 cells with IC50 values of 0.3 and 0.4 μM, respectively. © 2012 The American Chemical Society and American Society of Pharmacognosy. Source

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