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A Facile Synthesis of 2-Acyl and 2-Alkylaminobenzimidazoles for 5-Lipoxygenase Inhibitors
Han, Gyoonhee,Ha Lee, Jin,Hyun An, Mi,Hyun Choi, Eun,Park Choo, Hea-Young Japan Institute of Heterocyclic Chemistry 2006 Heterocycles Vol.70 No.1
<P>2-Acylaminobenzimidazoles (2a-r) have been synthesized from o-phenylenediamines (4) with benzoylcarbonimidodithioic acid dimethyl ester (5a) or dimethyl isobutyrylcarbonimidodithioic acid dimethyl ester (5b) in good yield. 2-Alkylaminobenzimidazoles could be prepared by the reaction of o-Phenylenediamines (4a, b) with benzyl isothiocyanate in moderate yields 8a, b or the reaction of 2-chlorobenzimidazole (9) with benzylamines (10a, b) in moderate yield 11a, b. Finally, the carbamate derivative of 2-aminobenzimidazole (13) was prepared by the reaction with pseudourea (12) in low yield. Most of the prepared analogues were evaluated in leukotriene inhibition assay and it found that benzamide derivatives (2a-i) are quite active among others.</P>
Discovery of Novel Histone Deacetylase (HDAC) Inhibitors for Anticancer Chemotherapy
Han, Gyoonhee 이화여자대학교 세포신호전달연구센터 2005 고사리 세포신호전달 심포지움 Vol. No.7
Main key players in Post-Gemone era have been considered to IDENTIFICATION of the functions of newly identified proteins and their chemical ligands. The latter will be more valuable but considered more challenged for the pharmaceutical industry. Combination of high throughput screening(HTS) and combinatorial chemistry plays quite well for these roles for many years in the major industry. Furthermore, introduction and development of new information technology(IT) into biotechnology(BT) area has been the new waves and considered a major breakthrough technology in drug discovery process. Bioinformatics and chemoinformatics play very well and have given a significant momentum in the early target discovery. Newly developed tools and softwares have afforded the clear idea in structure-activity relation(SAR) and more precise information in lead optimization, and eventually get us to save much time in decision making. Chromatin is the DNA-protein complex material and the majority of chromatin protein is composed of his tones, which assemble into nucleosomes. The histones are assisting in DNA packaging but also providing an important regulatory role. Histone deacetylase(HDAC) and histone acetyltransferase(HAT) are involved in the co-regulation of chromatin remodeling and the functional regulation of gene transcription. HDAC catalyzes deacetylation of a-amino group in lysines located near the N-terminal of core histone proteins. Abnormal recruitment of HDAC is related to carcinogenesis. Thus, the identification of potent HDAC inhibitors has been considered as a very intriguing approach for development of cancer chemotherapy. A number of natural and synthetic HDAC inhibitors have shown an anti-proliferative activity on tumor cells. Novel class of rigid core based hydroxamic acid HDAC inhibitors have been prepared and evaluated in enzymatic, cellular histone H4 hyperacetylation assaynhibition assay and the growth inhibitory activities on several human tumor cell lines, and some active inhibitors were evaluated in xenograft nude mouse model with MDA-MB-231 and ACHN tumor cells. Newly developed virtual tools and docking method were used for the structure based lead optimization and the rational drug design approaches will be introduced. The molecular mechanism study of the active small molecules based the cellular mechanism study also will be presented.
Lead Optimization of Novel Lactam Core HDAC Inhibitors for the Anti-cancer Chemotherapy
Han, Gyoonhee 이화여자대학교 세포신호전달연구센터 2009 고사리 세포신호전달 심포지움 Vol. No.11
Chromatin is the DNA-protein complex material and the majority of chromatin protein is composed of histones, which assemble into nucleosomes. The histones are assisting in DNA packaging but also providing an important regulatory role. Histone deacetylase(HDAC) and histone acetyltransferase(HAT) are involved in the co-regulation of chromatin remodeling and the functional regulation of gene transcription. HDAC catalyzes de acetylation of E-amino group in lysines located near the N-terminal of core histone proteins. Abnormal recruitment of HDAC is related to carcinogenesis. Thus, the identification of potent HDAC inhibitors has been considered as a very intriguing approach for development of cancer chemotherapy. Furthermore, some iso-types of HDAC also involve de acetylation of lysine residues of some proteins and increase the level of susceptibility to ubiquitination which leads to a protein degradation.(i.e. HDAC6 to tublin) Thus, there is some possibility to have iso-form selective HDAC inhibitor which can restore the level of anti-tumor biomolecules by epi-genetic control as well as the increase of the stability. A number of natural and synthetic HDAC inhibitors have shown an anti-proliferative activity on tumor cells. Identification of novel lactam based of HDAC inhibitors and their optimization for the discovery for the preclinical candidate will be presented. Novel class of rigid core based hydroxamic acid HDAC inhibitors have been prepared and evaluated in enzymatic, cellular histone H₄ hyperacetylation assay inhibition assay and the growth inhibitory activities on several human tumor cell lines, and some active inhibitors were evaluated in xenograft nude mouse model with MDA-MB-231 and ACHN tumor cells. Newly developed virtual tools and docking method were used for the structure based. lead optimization and the rational drug design approaches will be introduced.
CHOI, EUN-SUN,HAN, GYOONHEE,PARK, SONG-KYU,LEE, KIHO,KIM, HYUN-JUNG,CHO, SUNG-DAE,KIM, HWAN MOOK Spandidos Publications 2013 MOLECULAR MEDICINE REPORTS Vol.8 No.1
<P>Histone deacetylase (HDAC) inhibitors are emerging as potent anticancer agents due to their ability to induce apoptosis in various cancer cells, including prostate cancer cells. In the present study, we synthesized a novel HDAC inhibitor, A248, and investigated its apoptotic activity and molecular target in the DU145 and PC3 human prostate cancer cell lines. A248 inhibited the growth of DU145 and PC3 cells and induced apoptosis, as demonstrated by nuclear fragmentation and the accumulation of cells at subG1 phase of cell cycle. The treatment of DU145 and PC3 prostate cancer cells with A248 resulted in the downregulation of specificity protein?1 (Sp1) expression. Since the expression levels of survivin and Mcl-1 depend on Sp1, we also investigated the effects of A248 on survivin and Mcl-1 expression using western blot analysis and immunocytochemistry. The results showed that A248 markedly decreased the expression of survivin and Mcl-1. These data suggest that A248 has apoptotic activity in human prostate cancer cells and that Sp1 may be the molecular target of A248 treatment for inducing apoptosis in prostate cancer cells.</P>
Chun-Ho Park,Gyoonhee Han,김승현,김현영,Wan-Keun Ji,Jong-Hee Choi,천광우,Myung-Hwa Kim 대한화학회 2011 Bulletin of the Korean Chemical Society Vol.32 No.5
A series of potent tricyclic derivatives with a non-aromatic amide as potent PARP-1 inhibitors were successfully synthesized and their PARP-1 inhibitory activity was evaluated. Among the derivatives, 2-(1-propylpiperidin-4-yloxy)-7,8,9,10-tetrahydrophenanthridin-6(5H)-one 23c displayed potent activity in a PARP-1 enzymatic assay and cell-based assay (IC_50 = 0.142 μM, ED_50 = 0.90 μM) with good water solubility. Further, molecular modeling studies confirmed the obtained biological results
Shin, Ji-Ae,Han, Gyoonhee,Kim, Hyun-Jung,Kim, Hwan-Mook,Cho, Sung-Dae Lippincott Williams & Wilkins 2014 EUROPEAN JOURNAL OF CANCER PREVENTION Vol.23 No.4
Histone deacetylase inhibitors (HDACi) have been reported to have potent chemopreventive activity because of their effects on the inhibition of cell growth and apoptosis in human cancer cell lines. In the present study, we investigated the apoptotic effect of a novel HDACi, Ky2, and its molecular mechanism in MDA-MB-231 human breast cancer cells in vitro. The chemopreventive effects of Ky2 in MDA-MB-231 cells were evaluated using the MTS assay, anchorage-independent cell transformation assay, DAPI staining, western blot analysis, reverse transcriptase-PCR, and small interfering RNA. Ky2 enhanced histone acetylation and decreased cell viability. Ky2 induced apoptosis evidenced by nuclear condensation and fragmentation, the accumulation of sub-G1 phase, and caspase-dependent PARP cleavage. In addition, Ky2 released cytochrome c from mitochondria to cytosol through the regulation of mitochondria-related proteins (Bid, Bim, and Bcl-xL). Ky2 markedly decreased the level of Sp1 protein expression through both the decrease of Sp1 mRNA level and proteasome-dependent protein degradation. Interestingly, the apoptotic effect of Ky2 is more potent than SAHA, a well-known HDACi. Furthermore, the knockdown of Sp1 protein by Sp1-specific inhibitor, mithramycin A, and siRNA resulted in the alteration of truncated Bid and Bim to induce apoptosis. Furthermore, Ky2 significantly decreased TPA-induced or EGF-induced neoplastic cell transformation in JB6 cells. Our results suggest that Ky2 may be a potential chemopreventive and chemotherapeutic agent by modulating Sp1 in human breast cancer cells.
Chung, Kyung-Sook,Han, Gyoonhee,Kim, Bo-Kyung,Kim, Hwan-Mook,Yang, Jee Sun,Ahn, Jiwon,Lee, Kyeong,Song, Kyung-Bin,Won, Misun Springer 2013 Cancer chemotherapy and pharmacology Vol.72 No.6
<P>We investigated the action mechanism of a novel anticancer compound, KR28 (1-allyl-4-dodecanoyl-1-ethyl-piperazin-1-ium; bromide), to induce apoptosis of human prostate carcinoma PC-3 cells.</P>
Hwang, Jeong-Ha,Cha, Pu-Hyeon,Han, Gyoonhee,Bach, Tran The,Min, Do Sik,Choi, Kang-Yell Nature Publishing Group 2015 Experimental and molecular medicine Vol.47 No.3
<P>The Wnt/β-catenin pathway has a role in osteoblast differentiation and bone formation. We screened 100 plant extracts and identified an extract from <I>Euodia sutchuenensis</I> Dode (ESD) leaf and young branch as an effective activator of the Wnt/β-catenin pathway. ESD extract increased β-catenin levels and β-catenin nuclear accumulation in murine primary osteoblasts. The ESD extract also increased mRNA levels of osteoblast markers, including <I>RUNX2</I>, <I>BMP2</I> and <I>COL1A1</I>, and enhanced alkaline phosphatase (ALP) activity in murine primary osteoblasts. Both ESD extract-induced β-catenin increment and ALP activation were abolished by β-catenin knockdown, confirming that the Wnt/β-catenin pathway functions in osteoblast differentiation. ESD extract enhanced terminal osteoblast differentiation as shown by staining with Alizarin Red S and significantly increased murine calvarial bone thickness. This study shows that ESD extract stimulates osteoblast differentiation via the Wnt/β-catenin pathway and enhances murine calvarial bone formation <I>ex vivo</I>.</P>