Publications by authors named "Dohyeong Ko"

4 Publications

  • Page 1 of 1

Improved tumor-suppressive effect of OZ-001 combined with cisplatin mediated by mTOR/p70S6K and STAT3 inactivation in A549 human lung cancer cells.

Biomed Pharmacother 2021 Jul 28;142:111961. Epub 2021 Jul 28.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, Graduate School, Kyung Hee University, 26, Kyungheedae-ro, Seoul 02447, Republic of Korea. Electronic address:

We previously reported the anticancer activity of 4-(4-fluorobenzylcarbamoylmethyl)-3-(4-cyclohexylphenyl)-2-[3-(N,N-dimethylureido)-N'-methylpropylamino]-3,4-dihydroquinazoline (OZ-001), a T-type calcium channel (TTCC) blocker, against non-small cell lung cancer (NSCLC) in vitro and in vivo. Here, we evaluated the synergistic effect of OZ-001 and cisplatin on A549 human lung cancer cells and A549 xenograft mice. Our study demonstrated that treatment with OZ-001 and cisplatin sensitized A549 cells to cisplatin and significantly inhibited cell growth, increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, and induced poly (ADP-ribose) polymerase (PARP) cleavage in A549 cells and an A549 xenograft tumor mouse model. Moreover, our findings showed that mechanistic target of rapamycin (mTOR), ribosomal protein S6 kinase (p70S6K), and signal transducer and activator of transcription (STAT3) inactivation was required for apoptosis induced by the combination of OZ-001 and cisplatin in in vitro and in vivo experiments. Our results suggest that combined treatment with OZ-001 and cisplatin could potentiate antiproliferative effects via suppression of the mTOR/p70S6K and STAT3 pathways and may be considered a potential therapeutic agent for NSCLC.
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http://dx.doi.org/10.1016/j.biopha.2021.111961DOI Listing
July 2021

Discovery of N-amido-phenylsulfonamide derivatives as novel microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors.

Bioorg Med Chem Lett 2021 06 26;41:127992. Epub 2021 Mar 26.

Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

Our previous research showed that N-carboxy-phenylsulfonyl hydrazide (scaffold A) could reduce LPS-stimulated PGE levels in RAW 264.7 macrophage cells by an inhibition of mPGES-1 enzyme. However, a number of scaffold A derivatives showed the drawbacks such as the formation of regioisomers and poor liver metabolic stability. In order to overcome these synthetic and metabolic problems, therefore, we decided to replace N-carboxy-phenylsulfonyl hydrazide (scaffold A) with N-carboxy-phenylsulfonamide (scaffold B) or N-amido-phenylsulfonamide frameworks (scaffold C) as a bioisosteric replacement. Among them, MPO-0186 (scaffold C) inhibited the production of PGE (IC: 0.24 μM) in A549 cells via inhibition of mPGES-1 (IC: 0.49 μM in a cell-free assay) and was found to be approximately 9- and 8-fold more potent than MK-886 as a reference inhibitor, respectively. A molecular docking study theoretically suggests that MPO-0186 could inhibit PGE production by blocking the PGH binding site of mPGES-1 enzyme. Furthermore, MPO-0186 demonstrated good liver metabolic stability and no significant inhibition observed in clinically relevant CYP isoforms except CYP2C19. This result provides a potential starting point for the development of selective and potent mPGES-1 inhibitor with a novel scaffold.
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http://dx.doi.org/10.1016/j.bmcl.2021.127992DOI Listing
June 2021

Synthesis and cytotoxic effects of 2-thio-3,4-dihydroquinazoline derivatives as novel T-type calcium channel blockers.

Bioorg Med Chem 2020 06 14;28(11):115491. Epub 2020 Apr 14.

Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

In our previous work, a series of 2-amino-3,4-dihydroquinazoline derivativesusing an electron acceptor group was reported to be potent T-type calcium channel blockers and exhibit strong cytotoxic effects against various cancerous cell lines. To investigate the role of the guanidine moiety in the 2-amino-3,4-dihydroquinazoline scaffold as a pharmacophore for dual biological activity, a new series of 2-thio-3,4-dihydroquniazoline derivatives using an electron donor group at the C2-position was synthesized and evaluated for T-type calcium channel blocking activity and cytotoxic effects against two human cancerous cell lines (lung cancer A549 and colon cancer HCT-116). Among them, compound 6g showed potent inhibition of Ca3.2 currents (83% inhibition) at 10 µM concentrations. The compound also exhibited IC values of 5.0 and 6.4 µM against A549 and HCT-116 cell lines, respectively, which are comparable to the parental lead compound KYS05090. These results indicate that the isothiourea moiety similar to the guanidine moiety of 2-amino-3,4-dihydroquinazoline derivatives may be an essential pharmacophore for the desired biological activities. Therefore, our preliminary work can provide the opportunity to expand a chemical repertoire to improve affinity and selectivity for T-type calcium channels.
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http://dx.doi.org/10.1016/j.bmc.2020.115491DOI Listing
June 2020

KCP10043F Represses the Proliferation of Human Non-Small Cell Lung Cancer Cells by Caspase-Mediated Apoptosis via STAT3 Inactivation.

J Clin Med 2020 Mar 5;9(3). Epub 2020 Mar 5.

Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea.

We previously reported that 4-(4-fluorobenzylcarbamoylmethyl)-3-(4-cyclohexylphenyl)-2-[3-(-dimethylureido)--methylpropylamino]-3,4-dihydroquinazoline (KCP10043F) can induce G-phase arrest and synergistic cell death in combination with etoposide in lung cancer cells. Here, we investigated the underlying mechanism by which KCP10043F induces cell death in non-small cell lung cancer (NSCLC). Propidium iodide (PI) and annexin V staining revealed that KCP10043F-induced cytotoxicity was caused by apoptosis. KCP10043F induced a series of intracellular events: (1) downregulation of Bcl-2 and Bcl-xL and upregulation of Bax and cleaved Bid; (2) loss of mitochondrial membrane potential; (3) increase of cytochrome release; (4) cleavage of procaspase-8, procaspase-9, procaspase-3, and poly (ADP-ribose) polymerase (PARP). In addition, KCP10043F exhibited potent inhibitory effects on constitutive or interleukin-6 (IL-6)-induced signal transducer and activator of transcription (STAT3) phosphorylation and STAT3-regulated genes including survivin, Mcl-1, and cyclin D. Furthermore, STAT3 overexpression attenuated KCP10043F-induced apoptosis and the cleavage of caspase-9, caspase-3, and PARP. Docking analysis disclosed that KCP10043F could bind to a pocket in the SH2 domain of STAT3 and prevent STAT3 phosphorylation. The oral administration of KCP10043F decreased tumor growth in an A549 xenograft mouse model, as associated with the reduced phosphorylated STAT3, survivin, Mcl-1, and Bcl-2 expression and increased TUNEL staining and PARP cleavage in tumor tissues. Collectively, our data suggest that KCP10043F suppresses NSCLC cell growth through apoptosis induction via STAT3 inactivation.
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http://dx.doi.org/10.3390/jcm9030704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141374PMC
March 2020
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