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Jeong, Lak Shin,Alexander, Varughese,Choi, Won Jun,Chun, Jeong ha,Kim, Hea Ok,Jeon, Ji Hye,Tosh, Dilip K,Lee, Hyuk Woo,Chandra, Girish,Choi, Jung won 梨花女子大學校 藥學硏究所 2011 藥學硏究論文集 Vol.- No.21
The first synthesis of 4'-selenothymidine (1), a novel DNA building block, and 4'-seleno-AZT (2) was accomplished from 2-deoxy-d-ribose via stereoselective formation of 2-deoxy-4-seleno-d-furanose 17 and a Pummerer-type base condensation as key steps. 4'-Selenothymidine (1) was discovered to adopt the same 2'-endo/3'-exo conformation as thymidine, which is unusual in that 4'-selenouridine has the opposite conformation to that of uridine.
Development of Biologically Active Nucleosides from Carbohydrate Templates
Lak Shin Jeong 한국당과학회 2010 한국당과학회 학술대회 Vol.2010 No.1
Modified nucleosides are regarded as important templates in view of being extensively utilized as biodrugs as well as biological tools. They can be developed as viral and cellular polymerase inhibitors, antimetabolites, or modulators of receptor or enzyme functions. Also after being converted into oligonucleotides, they can be used in studying genome, siRNA, micro RNA, and so on. Especially, they have been used as drugs of choice for the treatment of viral diseases such as AIDS, hepatitis B/C virus (HBV/HCV), and herpetic virus (HSV). Despite of many clinically used drugs, the first generation nucleosides suffer from many drawbacks such as appearance of drug-resistance, toxicity, and metabolic unstability. To solve these problems, we have developed the 2nd generation nucleosides in which furanose oxygen was substituted with sulfur or methylene (CH2), among which several compounds are being developed as antitumor, anti-glaucoma, and anti-inflammatory agents. Recently, we discovered the novel template as next generation nucleosides, 4'-selenonucleosides with various antiviral and antitumor activities. In this symposium, the first, second, and third generation nucleosides developed in our laboratory will be presented in detail.
Jeong, Lak Shin,Choe, Seung Ah,Gunaga, Prashantha,Kim, Hea Ok,Lee, Hyuk Woo,Lee, Sang Kook,Tosh, Dilip K.,Patel, Amit,Palaniappan, Krishnan K.,Gao, Zhan-Guo,Jacobson, Kenneth A.,Moon, Hyung Ryong 이화여자대학교 약학연구소 2008 藥學硏究論文集 Vol.- No.18
Truncated D-4'-thioadenosine derivatives lacking the 4'-hydroxymethylene moiety were synthesized starting from D-mannose, using cyclization to the 4-thiosugar and one-step conversion of the diol to the acetate as key steps At the human A₃ adenosine receptor (AR), N^(6)-substituted purine analogues bound potently and selectively and acted as antagonists in a cyclic AMP functional assay An N^(6)-(3-chlorobenzyl)purine analogue 9b displayed a K, value of 1 66 nM at the human A₃ AR Thus, truncated D-4'-thioadenosine is an excellent template for Ihe design of novel A₃ AR antagonists to act at both human and murine species.
Lak Shin, Jeong,In-Young, Choi,Jae-Chul, Lee,Chung, Ju,SunYoung, Hwang,Geum-sil, Cho,Hyuk Woo, Lee,Won Jun, Choi,Won-ki, Kim 梨花女子大學校 藥學硏究所 2012 藥學硏究論文集 Vol.- No.22
A3 adenosine receptor (A3AR) is recognized as a novel therapeutic target for ischemic injury; however, the mechanism underlying anti-ischemic protection by the A3AR agonist remains unclear. Here, we report that 2-chloro-N(6)-(3-iodobenzyl)-5'-N-methylcarbamoyl-4'-thioadenosine (LJ529), a selective A3AR agonist, reduces inflammatory responses that may contribute to ischemic cerebral injury. Postischemic treatment with LJ529 markedly reduced cerebral ischemic injury caused by 1.5-hour middle cerebral artery occlusion, followed by 24-hour reperfusion in rats. This effect was abolished by the simultaneous administration of the A3AR antagonist MRS1523, but not the A2AAR antagonist SCH58261. LJ529 prevented the infiltration/migration of microglia and monocytes occurring after middle cerebral artery occlusion and reperfusion, and also after injection of lipopolysaccharides into the corpus callosum. The reduced migration of microglia by LJ529 could be related with direct inhibition of chemotaxis and down-regulation of spatiotemporal expression of Rho GTPases (including Rac, Cdc42, and Rho), rather than by biologically relevant inhibition of inflammatory cytokine/chemokine release (eg, IL-1β, TNF-α, and MCP-1) or by direct inhibition of excitotoxicity/oxidative stress (not affected by LJ529). The present findings indicate that postischemic activation of A3AR and the resultant reduction of inflammatory response should provide a promising therapeutic strategy for the treatment of ischemic stroke
Jeong, Lak Shin,Yoo, Su Jeong,Lee, Kang Man,Koo, Mi Jeong,Choi, Won Jun,Kim, Hea Ok,Moon, Hyung Ryong,Lee, Min Young,Park, Jae Gyu,Lee, Sang Kook,Chun, Moon Woo 梨花女子大學校 藥學硏究所 2003 藥學硏究論文集 Vol.- No.12
Fluoroneplanocin A (12) was designed as a novel mechanism-based inhibitor of S-adenosylhomocysteine hydrolase (SAH) and efficiently synthesized via an electrophilic vinyl fluorination reaction (n-BuLi, N-fluorobenzenesulfonimide at -78℃). Fluoroneplanocin A exhibited 2-fold more potent SAH Inhibitory activity than the parent neplanocin A. A new mechanism of irreversible Inhibition discovered in this work might provide new alternatives in the design of a different class of antiviral agents operating via SAH inhibition.
Jeong, Lak Shin 이화여자대학교 세포신호전달연구센터 2007 고사리 세포신호전달 심포지움 Vol. No.9
S-Adenosylhomocysteine hydrolase catalyzes the hydrolysis of S-adenosylhomocysteine to adenosine and L-homocysteine. Inhibition of this enzyme accumulates S-adenosylhomocysteine, which in turn inhibits S-adenosyl-L-methionine dependent transmethylation, resulting in no formation of the capped methylated structure at the 5'-terminus of viral mRNA. Thus, S-adenosylhomocysteine hydrolase has been an attractive target for the development of broad spectrum of antiviral agents. Neplanocin A is a potent inhibitor of S-adenosylhomocysteine hydrolase. Neplanocin A inactivates the enzyme by depleting a cofactor(NAD^(+)) and its inhibition is reversed by incubation with with NAD^(+). Besides the cofactor depletion mechanism, we thought that neplanocin A can form a covalent bond with an active site of the enzyme in a Michael type reaction after the incubation with enzyme, but its irreversible action can be easily reversed by the presence of acidic 4'-hydrogen. Therefore, if we put the halogen atom into the C6 position of the neplanocin A, the resulting halo-neplanocin A anlogues might inhibit the enzyme irreversibly because of no acidic hydrogen at the 4'-position. As expected, fluoro-neplanocin A inhibited the enzyme irreversibly at the submicromolar concentration unlike neplanocin A showing the reversible inhibition. Synthesis and broad-spectrum of antiviral activity of the target compounds will be discussed in this symposium.
Jeong, Lak Shin,Shantanu Pal,Choe, Seung Ah,Choi, Won Jun,Kenneth A. Jacobson,Zhan-Guo Gao,Athena M. Klutz,Xiyan Hou,Kim, Hea Ok,Lee, Hyuk Woo,Lee, Sang Kook,Dilip K. Tosh,Moon, Hyung Ryong 이화여자대학교 약학연구소 2009 藥學硏究論文集 Vol.- No.19
Novel D- and L-4´-thioadenosine derivatives lacking the 4´-hydroxymethyl moiety were synthesized, starting from D-mannose and D-gulonic γ-lactone, respectively, as potent and selective species-independent A₃ adenosine receptor (AR) antagonists. Among the novel 4´-truncated 2-H nucleosides tested, a N^(6)-(3-chlorobenzyl) derivative 7c was the most potent at the human A₃ AR (K_(i) = 1.5 nM), but a N^(6)-(3-bromobenzyl) derivative 7d showed the optimal species-independent binding affinity.
Lak Shin, Jeong,Dilip K. Tosh,Won Jun, Choi,Sang Kook, Lee,You-Jin, Kang,Sun, Choi,Jin Hee, Lee,Hankil, Lee,Hyuk Woo, Lee,Hea Ok, Kim 이화여자대학교 약학연구소 2010 藥學硏究論文集 Vol.- No.20
The first synthesis of 2'-deoxy-2'-fluoro-4'-selenoarabinofuranosyl pyrimidines as potent anticancer agents was accomplished using the DAST fluorination as a key step. It was first revealed that selenium atom participated in the DAST fluorination of 4'-selenonucleosides and that conformational bias induced by bulky selenium acted as a decisive factor in the DAST fluorination. Among compounds tested, 2'-F-4'-seleno-ara-C (4a) exhibited highly potent anticancer activity in all cancer cell lines tested and was more potent than ara-C (1).
Synthesis and Antiviral Activity of $2^1$-Fluorohexopyranosyl Nucleosides
Jeong, Lak-Shin,Lee, Jong-Eun,Kim, Hea-Ok,Chun, Moon-Woo The Pharmaceutical Society of Korea 1998 Archives of Pharmacal Research Vol.21 No.3
$2^1$-Fluorohexopyranosyl nucleosides 1a and 1b which contained a bioisosteric double bond and a fluorine were synthesized in 12 steps, starting from D-galactose. During diethylaminosulfur trifluoride (DAST) fluorination, retention of stereochemistry was observed through the participation of methoxy or chloro group at the 6-posiition of the purine base. The final nucleosides 1a and 1b were found to be inactive against HIV-1 and HSV-1,2.