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Synthesis and biological evaluation of indazole-4,7-dione derivatives as novel BRD4 inhibitors
Yoo, Minjin,Yoo, Miyoun,Kim, Ji Eun,Lee, Heung Kyoung,Lee, Chong Ock,Park, Chi Hoon,Jung, Kwan-Young The Pharmaceutical Society of Korea 2018 Archives of Pharmacal Research Vol.41 No.1
Bromodomain-containing protein 4 (BRD4) is known to regulate the expression of c-Myc to control the proliferation of cancer cells. Therefore, development of small-molecule inhibitors targeting the bromodomain has been widely studied. However, some clinical trials on BRD4 inhibitors have shown its drawbacks such as toxicity including the loss of organ weight. Here, we report the development of the novel and promising scaffold, 1H-indazol-4,7-dione, as a bromodomain inhibitor and synthesized derivatives for the inhibition of binding of bromodomain to acetylated histone peptide. Through this effort, we obtained 6-chloro-5-((2,6-difluorophenyl)amino)-1H-indazole-4,7-dione (5i), which showed a highly potent activity with a half-maximal inhibitory concentration (<TEX>$IC_{50}$</TEX>) of 60 nM. The in vivo xenograft assay confirmed that the 1H-indazol-4,7-dione compound reduced the tumor size significantly. These results show that the 1H-indazol-4,7-dione scaffold is highly potent against bromodomain.
Kim, Dockyu,Yoo, Miyoun,Choi, Ki Young,Kang, Beom Sik,Kim, Tai Kyoung,Hong, Soon Gyu,Zylstra, Gerben J,Kim, Eungbin American Society for Microbiology 2011 Applied and environmental microbiology Vol.77 No.23
<P>The metabolically versatile Rhodococcus sp. strain DK17 is able to grow on tetralin and indan but cannot use their respective desaturated counterparts, 1,2-dihydronaphthalene and indene, as sole carbon and energy sources. Metabolite analyses by gas chromatography-mass spectrometry and nuclear magnetic resonance spectrometry clearly show that (i) the meta-cleavage dioxygenase mutant strain DK180 accumulates 5,6,7,8-tetrahydro-1,2-naphthalene diol, 1,2-indene diol, and 3,4-dihydro-naphthalene-1,2-diol from tetralin, indene, and 1,2-dihydronaphthalene, respectively, and (ii) when expressed in Escherichia coli, the DK17 o-xylene dioxygenase transforms tetralin, indene, and 1,2-dihydronaphthalene into tetralin cis-dihydrodiol, indan-1,2-diol, and cis-1,2-dihydroxy-1,2,3,4-tetrahydronaphthalene, respectively. Tetralin, which is activated by aromatic hydroxylation, is degraded successfully via the ring cleavage pathway to support growth of DK17. Indene and 1,2-dihydronaphthalene do not serve as growth substrates because DK17 hydroxylates them on the alicyclic ring and further metabolism results in a dead-end metabolite. This study reveals that aromatic hydroxylation is a prerequisite for proper degradation of bicyclics with aromatic and alicyclic rings by DK17 and confirms the unique ability of the DK17 o-xylene dioxygenase to perform distinct regioselective hydroxylations.</P>
Toxicity of the recombinant human hyaluronidase ALT-BC4 on embryonic development
( Ji Hye Lee ),( Miyoun Yoo ),( Sang Mee Lee ),( Soon-jae Park ),( Tae Young Kil ),( Min Kyu Kim ) 한국축산학회(구 한국동물자원과학회) 2021 한국축산학회지 Vol.63 No.2
Cumulus-oocyte complexes (COCs), which contain immature oocytes, are matured in vitro for in vitro embryo production. Oocyte and cumulus cells are then separated using hyaluronidase. To date, there have only been a few reported cases of the toxic effects of hyaluronidase on porcine oocytes. The aim of this study was to compare the effects of bovine testis-derived hyaluronidase and recombinant human hyaluronidase on oocyte denudation and quality. Porcine COCs were matured for 44 h and denuded using different hyaluronidase concentrations and exposure times. Then, oocytes were activated by electrical parthenogenesis. In experiment 1, COCs were denuded using bovine-derived, ovine-derived (Hirax), and human recombinant (ALT-BC4) hyaluronidases for 10 and 20 min. In experiment 2, bovine-derived and human recombinant (ALT-BC4 and ICSI Cumulase<sup>®</sup>) hyaluronidases were used to denude the COCs for 2 and 20 min. In both experiments the oocytes were all completely denuded, and there was no degeneration. Rate of embryo development was significantly increased in group treated ALT-BC4 for 2 min and not significantly different in other treatment groups. In general it slightly decreased with longer exposure times. These results have confirmed that different sources of hyaluronidase do not have detrimental effects on the quality of porcine oocytes and suggest that the human recombinant hyaluronidase ALT-BC4 is suitable for oocyte denudation with an increased blastocyst rate.
Kim, Dockyu,Choi, Ki Young,Yoo, Miyoun,Choi, Jung Nam,Lee, Choong Hwan,Zylstra, Gerben J,Kang, Beom Sik,Kim, Eungbin Springer International 2010 Applied microbiology and biotechnology Vol.86 No.6
<P>Escherichia coli cells expressing Rhodococcus DK17 o-xylene dioxygenase genes were used for bioconversion of m-xylene. Gas chromatography-mass spectrometry analysis of the oxidation products detected 3-methylbenzylalcohol and 2,4-dimethylphenol in the ratio 9:1. Molecular modeling suggests that o-xylene dioxygenase can hold xylene isomers at a kink region between alpha6 and alpha7 helices of the active site and alpha9 helix covers the substrates. m-Xylene is unlikely to locate at the active site with a methyl group facing the kink region because this configuration would not fit within the substrate-binding pocket. The m-xylene molecule can flip horizontally to expose the meta-position methyl group to the catalytic motif. In this configuration, 3-methylbenzylalcohol could be formed, presumably due to the meta effect. Alternatively, the m-xylene molecule can rotate counterclockwise, allowing the catalytic motif to hydroxylate at C-4 yielding 2,4-dimethylphenol. Site-directed mutagenesis combined with structural and functional analyses suggests that the alanine-218 and the aspartic acid-262 in the alpha7 and the alpha9 helices play an important role in positioning m-xylene, respectively.</P>
Biotechnological Potential of Rhodococcus Biodegradative Pathways
( Dockyu Kim ),( Ki Young Choi ),( Miyoun Yoo ),( Gerben J. Zylstra ),( Eungbin Kim ) 한국미생물생명공학회(구 한국산업미생물학회) 2018 Journal of microbiology and biotechnology Vol.28 No.7
The genus Rhodococcus is a phylogenetically and catabolically diverse group that has been isolated from diverse environments, including polar and alpine regions, for its versatile ability to degrade a wide variety of natural and synthetic organic compounds. Their metabolic capacity and diversity result from their diverse catabolic genes, which are believed to be obtained through frequent recombination events mediated by large catabolic plasmids. Many rhodococci have been used commercially for the biodegradation of environmental pollutants and for the biocatalytic production of high-value chemicals from low-value materials. Recent studies of their physiology, metabolism, and genome have broadened our knowledge regarding the diverse biotechnological applications that exploit their catabolic enzymes and pathways.
Park, Sun Jun,Kim, Eunjin,Yoo, Miyoun,Lee, Joo-Youn,Park, Chi Hoon,Hwang, Jong Yeon,Ha, Jae Du Elsevier 2017 Bioorganic & medicinal chemistry letters Vol.27 No.18
<P><B>Abstract</B></P> <P>A novel 6-aminopurine scaffold bearing an <I>N</I>9-<I>cis</I>-cyclobutyl moiety was designed using structure-based molecular design based on two known CDK inhibitors, dinaciclib and Cmpd-27. A series of novel 6-aminopurine compounds was prepared for structure–activity relationship (SAR) studies of CDK2 and CDK5 inhibitors. Among the compounds synthesized, compound <B>8l</B> displayed potent CDK2 and CDK5 inhibitory activities with low nanomolar ranges (IC<SUB>50</SUB> =2.1 and 4.8nM, respectively) and showed moderate cytotoxicity in HCT116 colon cancer and MCF7 breast cancer cell lines. Here, we report the synthesis and evaluation of novel 6-aminopurine derivatives and present molecular docking models of compound <B>81</B> with CDK2 and CDK5.</P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
Kim, Young Hun,Kim, Minsung,Yoo, Miyoun,Kim, Ji Eun,Lee, Heung Kyoung,Heo, Jung-Nyoung,Lee, Chong Ock,Yoo, Minjin,Jung, Kwan-Young,Yun, Chang-Soo,Moon, Sung Woong,Chang, Hye Kyung,Chung, Chul-Woong,Py Elsevier 2018 Biochemical and biophysical research communication Vol.503 No.2
<P><B>Abstract</B></P> <P>Bromodomain-containing protein 4 (Brd4) is known to play a key role in tumorigenesis. It binds acetylated histones to regulate the expression of numerous genes. Because of the importance of brd4 in tumorigenesis, much research has been undertaken to develop brd4 inhibitors with therapeutic potential. As a result, various scaffolds for bromodomain inhibitors have been identified. To discover new scaffolds, we performed mid-throughput screening using two different enzyme assays, alpha-screen and ELISA. We found a novel bromodomain inhibitor with a unique scaffold, aristoyagonine. This natural compound showed inhibitory activity <I>in vitro</I> and tumor growth inhibition in a Ty82-xenograft mouse model. In addition, we tested Brd4 inhibitors in gastric cancer cell lines, and found that aristoyagonine exerted cytotoxicity not only in I-BET-762-sensitive cancer cells, but also in I-BET-762-resistant cancer cells. This is the first paper to describe a natural compound as a Brd4 bromodomain inhibitor.</P>