Publications by authors named "Hea Ok Kim"

75 Publications

Design, Synthesis, and Anti-RNA Virus Activity of 6'-Fluorinated-Aristeromycin Analogues.

J Med Chem 2019 07 20;62(13):6346-6362. Epub 2019 Jun 20.

Research Institute of Pharmaceutical Sciences, College of Pharmacy , Seoul National University , Seoul 151-742 , Korea.

The 6'-fluorinated aristeromycins were designed as dual-target antiviral compounds aimed at inhibiting both the viral RNA-dependent RNA polymerase (RdRp) and the host cell -adenosyl-l-homocysteine (SAH) hydrolase, which would indirectly target capping of viral RNA. The introduction of a fluorine at the 6'-position enhanced the inhibition of SAH hydrolase and the activity against RNA viruses. The adenosine and -methyladenosine analogues showed potent inhibition against SAH hydrolase, while only the adenosine derivatives exhibited potent antiviral activity against all tested RNA viruses such as Middle East respiratory syndrome-coronavirus (MERS-CoV), severe acute respiratory syndrome-coronavirus, chikungunya virus, and/or Zika virus. 6',6'-Difluoroaristeromycin () showed the strongest antiviral effect for MERS-CoV, with a ∼2.5 log reduction in infectious progeny titer in viral load reduction assay. The phosphoramidate prodrug also demonstrated potent broad-spectrum antiviral activity, possibly by inhibiting the viral RdRp. This study shows that 6'-fluorinated aristeromycins can serve as starting points for the development of broad-spectrum antiviral agents that target RNA viruses.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7075649PMC
July 2019

Structure-activity relationships of 2'-modified-4'-selenoarabinofuranosyl-pyrimidines as anticancer agents.

Eur J Med Chem 2014 Aug 14;83:208-25. Epub 2014 Jun 14.

College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea; College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea. Electronic address:

Based on the potent anticancer activity of the D-arabino-configured cytosine nucleoside ara-C, novel 2'-substituted-4'-selenoarabinofuranosyl pyrimidines 3a-3u, comprising azido, fluoro, and hydroxyl substituents at C-2' were designed, synthesized, and evaluated for anticancer activity. The 2'-azido group was stereoselectively introduced by the Mitsunobu reaction using diphenylphosphoryl azide (DPPA), and the 2'-fluoro group was stereoselectively introduced through the double inversions of stereochemistry via the episelenium intermediate, which was formed by the participation of the selenium atom. Among the compounds tested, the 2'-fluoro derivative 3t (X = NH2, Y = H, R = F) was found to be the most potent anticancer agent and showed more potent anticancer activity than the control, ara-C in all tested human cancer cell lines (HCT116, A549, SNU638, T47D, and PC-3) except the leukemia cell lines (K562). The anticancer activity of the 2'-substituted-4'-selenonucleosides is in the following order: 2'-F > 2'-OH > 2'-N3.
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http://dx.doi.org/10.1016/j.ejmech.2014.06.031DOI Listing
August 2014

Synthesis and anti-renal fibrosis activity of conformationally locked truncated 2-hexynyl-N(6)-substituted-(N)-methanocarba-nucleosides as A3 adenosine receptor antagonists and partial agonists.

J Med Chem 2014 Feb 5;57(4):1344-54. Epub 2014 Feb 5.

Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul 151-742, Korea.

Truncated N(6)-substituted-(N)-methanocarba-adenosine derivatives with 2-hexynyl substitution were synthesized to examine parallels with corresponding 4'-thioadenosines. Hydrophobic N(6) and/or C2 substituents were tolerated in A3AR binding, but only an unsubstituted 6-amino group with a C2-hexynyl group promoted high hA2AAR affinity. A small hydrophobic alkyl (4b and 4c) or N(6)-cycloalkyl group (4d) showed excellent binding affinity at the hA3AR and was better than an unsubstituted free amino group (4a). A3AR affinities of 3-halobenzylamine derivatives 4f-4i did not differ significantly, with Ki values of 7.8-16.0 nM. N(6)-Methyl derivative 4b (Ki = 4.9 nM) was a highly selective, low efficacy partial A3AR agonist. All compounds were screened for renoprotective effects in human TGF-β1-stimulated mProx tubular cells, a kidney fibrosis model. Most compounds strongly inhibited TGF-β1-induced collagen I upregulation, and their A3AR binding affinities were proportional to antifibrotic effects; 4b was most potent (IC50 = 0.83 μM), indicating its potential as a good therapeutic candidate for treating renal fibrosis.
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http://dx.doi.org/10.1021/jm4015313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954500PMC
February 2014

Fluorocyclopentenyl-cytosine with broad spectrum and potent antitumor activity.

J Med Chem 2012 May 1;55(9):4521-5. Epub 2012 May 1.

Department of Bioinspired Science and College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.

On the basis of the potent biological activity of cyclopentenyl-pyrimidines, fluorocyclopentenyl-pyrimidines were designed and synthesized from D-ribose. Among these, the cytosine derivative 5a showed highly potent antigrowth effects in a broad range of tumor cell lines and very potent antitumor activity in a nude mouse tumor xenograft model implanted with A549 human lung cancer cells. However, its 2'-deoxycytidine derivative 5b did not show any antigrowth effects, indicating that 2'-hydroxyl group is essential for the biological activity.
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http://dx.doi.org/10.1021/jm3004009DOI Listing
May 2012

Structure-activity relationships of truncated C2- or C8-substituted adenosine derivatives as dual acting A₂A and A₃ adenosine receptor ligands.

J Med Chem 2012 Jan 28;55(1):342-56. Epub 2011 Dec 28.

Laboratory of Medicinal Chemistry, College of Pharmacy, and Department of Bioinspired Science, Ewha Womans University, Seoul 120-750, Korea.

Truncated N(6)-substituted-4'-oxo- and 4'-thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A(2A) and A(3) adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA(2A)AR, but hydrophobic C8 substitution abolished binding at the hA(2A)AR. However, most of synthesized compounds displayed medium to high binding affinity at the hA(3)AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA(2A)AR agonists. C2 substitution probed geometrically through hA(2A)AR docking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA(2A)AR agonist and hA(3)AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases.
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http://dx.doi.org/10.1021/jm201229jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266722PMC
January 2012

Stereoselective synthesis of MLN4924, an inhibitor of NEDD8-activating enzyme.

J Org Chem 2011 May 21;76(9):3557-61. Epub 2011 Mar 21.

Department of Bioinspired Science and Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.

MLN4924 (1), which is in clinical trials as an anticancer agent, was stereoselectively synthesized from d-ribose via a route involving stereoselective reduction, regioselective cleavage of an isopropylidene moiety, and selective displacement of a cyclic sulfate moiety as key steps.
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http://dx.doi.org/10.1021/jo2001897DOI Listing
May 2011

Discovery of New Human A(2A) Adenosine Receptor Agonists: Design, Synthesis, and Binding Mode of Truncated 2-Hexynyl-4'-thioadenosine.

ACS Med Chem Lett 2010 Sep;2010(9):516-520

Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.

The truncated C2- and C8-substituted-4'-thioadenosine derivatives 4a-d were synthesized from D-mannose, using palladium-catalyzed cross coupling reactions as key steps. In this study, an A(3) adenosine receptor (AR) antagonist, truncated 4'-thioadenosine derivative 3 was successfully converted into a potent A(2A)AR agonist 4a (K(i) = 7.19 ± 0.6 nM) by appending a 2-hexynyl group at the C2-position of a derivative of 3 that was N(6)-substituted. However, C8-substitution greatly reduced binding affinity at the human A(2A)AR. All synthesized compounds 4a-d maintained their affinity at the human A(3)AR, but 4a was found to be a competitive A(3)AR antagonist/A(2A)AR agonist in cyclic AMP assays. This study indicates that the truncated C2-substituted-4'-thioadenosine derivatives 4a and 4b can serve as a novel template for the development of new A(2A)AR ligands.
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http://dx.doi.org/10.1021/ml1001823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030271PMC
September 2010

X-ray crystal structure and binding mode analysis of human S-adenosylhomocysteine hydrolase complexed with novel mechanism-based inhibitors, haloneplanocin A analogues.

J Med Chem 2011 Feb 12;54(4):930-8. Epub 2011 Jan 12.

College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.

The X-ray crystal structure of human S-adenosylhomocysteine (AdoHcy) hydrolase was first determined as a tetrameric form bound with the novel mechanism-based inhibitor fluoroneplanocin A (4b). The crystallized enzyme complex showed the closed conformation and turned out to be the intermediate of mechanism-based inhibition. It confirmed that the cofactor depletion by 3'-oxidation of fluoroneplanocin A contributes to the enzyme inhibition along with the irreversible covalent modification of AdoHcy hydrolase. In addition, a series of haloneplanocin A analogues (4b-e and 5b-e) were designed and synthesized to characterize the binding role and reactivity of the halogen substituents and the 4'-CH(2)OH group. The biological evaluation and molecular modeling studies identified the key pharmacophores and structural requirements for the inhibitor binding of AdoHcy hydrolase. The inhibitory activity was decreased as the size of the halogen atom increased and/or if the 4'-CH(2)OH group was absent. These results could be utilized to design new therapeutic agents operating via AdoHcy hydrolase inhibition.
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http://dx.doi.org/10.1021/jm1010836DOI Listing
February 2011

Design, synthesis, and binding of homologated truncated 4'-thioadenosine derivatives at the human A3 adenosine receptors.

Bioorg Med Chem 2010 Oct 14;18(19):7015-21. Epub 2010 Aug 14.

Department of Bioinspired Science, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.

We synthesized homologated truncated 4'-thioadenosine analogues 3 in which a methylene (CH(2)) group was inserted in place of the glycosidic bond of a potent and selective A(3) adenosine receptor antagonist 2. The analogues were designed to induce maximum binding interaction in the binding site of the A(3) adenosine receptor. However, all homologated nucleosides were devoid of binding affinity at all subtypes of adenosine receptors, indicating that free rotation through the single bond allowed the compound to adopt an indefinite number of conformations, disrupting the favorable binding interaction essential for receptor recognition.
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http://dx.doi.org/10.1016/j.bmc.2010.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724522PMC
October 2010

Synthesis and anti-hepatitis C virus (HCV) activity of 3'-C-substituted-methyl pyrimidine and purine nucleosides.

Bioorg Med Chem 2010 Jul 31;18(13):4812-20. Epub 2010 May 31.

Department of Bioinspired Science, Ewha Womans University, 11-1 Seodaemun-gu, Daehyun-dong, Seoul 120-750, Republic of Korea.

On the basis of potent anti-hepatitis C virus (HCV) activity of 2'-C-hydroxymethyladenosine, 3'-C-substituted-methyl-ribofuranosyl pyrimidine and purine nucleosides were designed and synthesized from D-xylose. Among compounds tested, all adenine analogues, 4a, 4d, and 4g showed significant anti-HCV activity in a replicon-based cell assay irrespective of the substituent (Y=OH, N₃, or F) at the 3'-C-substituted methyl position, among which 4g (Y=N₃) was the most potent, but it is also cytotoxic. This study guarantees the 3'-C-substituted-methyl nucleoside serves as a new template for the development of new anti-HCV agents.
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http://dx.doi.org/10.1016/j.bmc.2010.05.002DOI Listing
July 2010

A new DNA building block, 4'-selenothymidine: synthesis and modification to 4'-seleno-AZT as a potential anti-HIV agent.

Org Lett 2010 May;12(10):2242-5

Department of Bioinspired Science and Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.

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.
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http://dx.doi.org/10.1021/ol1005906DOI Listing
May 2010

Design and synthesis of N(6)-substituted-4'-thioadenosine-5'-uronamides as potent and selective human A(3) adenosine receptor agonists.

Bioorg Med Chem 2009 Dec 12;17(23):8003-11. Epub 2009 Oct 12.

Department of Bioinspired Science and Division of Life and Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.

On the basis of a bioisosteric rationale, 4'-thionucleoside analogues of IB-MECA (N(6)-(3-Iodo-benzyl)-9-(5'-methylaminocarbonyl-beta-d-ribofuranosyl)adenine), which is a potent and selective A(3) adenosine receptor (AR) agonist, were synthesized from d-gulonic acid gamma-lactone. The 4'-thio analogue (5h) of IB-MECA showed extremely high binding affinity (K(i)=0.25 nM) at the human A(3)AR and was more potent than IB-MECA (K(i)=1.4 nM). Bulky substituents at the 5'-uronamide position, such as cyclohexyl and 2-methylbenzyl, in this series of 2-H nucleoside derivatives were tolerated in A(3)AR binding, although small alkyl analogues were more potent.
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http://dx.doi.org/10.1016/j.bmc.2009.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2797373PMC
December 2009

Discovery of a new template for anticancer agents: 2'-deoxy-2'-fluoro-4'-selenoarabinofuranosyl-cytosine (2'-F-4'-seleno-ara-C).

J Med Chem 2009 Sep;52(17):5303-6

Department of Bioinspired Science, Division of Life and Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul, Korea.

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).
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http://dx.doi.org/10.1021/jm900852bDOI Listing
September 2009

Structure-activity relationships of truncated adenosine derivatives as highly potent and selective human A3 adenosine receptor antagonists.

Bioorg Med Chem 2009 May 25;17(10):3733-8. Epub 2009 Mar 25.

Department of Bioinspired Science and Division of Life and Pharmaceutical Sciences, Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.

On the basis of potent and selective binding affinity of truncated 4'-thioadenosine derivatives at the human A(3) adenosine receptor (AR), their bioisosteric 4'-oxo derivatives were designed and synthesized from commercially available 2,3-O-isopropylidene-D-erythrono lactone. The derivatives tested in AR binding assays were substituted at the C2 and N(6) positions. All synthesized nucleosides exhibited potent and selective binding affinity at the human A(3) AR. They were less potent than the corresponding 4'-thio analogues, but showed still selective to other subtypes. The 2-Cl series generally were better than the 2-H series in view of binding affinity and selectivity. Among compounds tested, compound 5d (X=Cl, R=3-bromobenzyl) showed the highest binding affinity (K(i)=13.0+/-6.9 nM) at the hA(3) AR with high selectivity (at least 88-fold) in comparison to other AR subtypes. Like the corresponding truncated 4'-thio series, compound 5d antagonized the action of an agonist to inhibit forskolin-stimulated adenylate cyclase in hA(3) AR-expressing CHO cells. Although the 4'-oxo series were less potent than the 4'-thio series, this class of human A(3) AR antagonists is also regarded as another good template for the design of A(3) AR antagonists and for further drug development.
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http://dx.doi.org/10.1016/j.bmc.2009.03.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578599PMC
May 2009

Design and synthesis of novel 2',3'-dideoxy-4'-selenonucleosides as potential antiviral agents.

Bioorg Med Chem 2008 Dec 17;16(23):9891-7. Epub 2008 Oct 17.

Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.

On the basis of potent anti-HIV activity of 2',3'-dideoxynucleosides (ddNs), their bioisosteric analogues, 2',3'-dideoxy-4'-selenonucleosides (4'-seleno-ddNs) were first synthesized from a chiral template, d-glutamic acid using stereoselective ring-closure reaction of the dimesylate with Se(2-) and Pummerer type condensation of the selenoxide with nucleobases as key steps. X-ray crystallographic analysis indicated that 4'-seleno-ddNs adopted the same C2'-endo/C3'-exo (South) conformation as anti-HIV active ddNs, but did not show anti-HIV activity, indicating that RT seems to prefer the C2'-exo/C3'-endo (North) conformation on binding with their triphosphates.
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http://dx.doi.org/10.1016/j.bmc.2008.10.034DOI Listing
December 2008

Structure-activity relationships of truncated D- and l-4'-thioadenosine derivatives as species-independent A3 adenosine receptor antagonists.

J Med Chem 2008 Oct 24;51(20):6609-13. Epub 2008 Sep 24.

Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.

Novel D- and l-4'-thioadenosine derivatives lacking the 4'-hydroxymethyl moiety were synthesized, starting from d-mannose and d-gulonic gamma-lactone, respectively, as potent and selective species-independent A 3 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 A 3 AR (K i = 1.5 nM), but a N(6)-(3-bromobenzyl) derivative 7d showed the optimal species-independent binding affinity.
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http://dx.doi.org/10.1021/jm8008647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616494PMC
October 2008

Design and synthesis of truncated 4'-thioadenosine derivatives as potent and selective A3 adenosine receptor antagonists.

Nucleic Acids Symp Ser (Oxf) 2008 (52):641-2

Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.

We have established structure-activity relationships of novel truncated D-4'-thioadenosine derivatives from D-mannose as potent and selective A(3) adenosine receptor (AR) antagonists. At the human A(3) AR, most of N(6)-substituted analogues showed high potency and selectivity and acted as pure antagonists in a cyclic AMP functional assay. Among compounds tested, 2-chloro-N(6)-3-chlorobenzyl and N(6)-3-chlorobenzyl analogues displayed very high binding affinities (K(i) = 1.66 nM and 1.5 nM, respectively) at the human A(3) AR. Truncated 4'-thioadenosine derivatives studied here are regarded as an excellent template for the design of novel A(3) AR antagonists to act at both human and murine species.
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http://dx.doi.org/10.1093/nass/nrn324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3097420PMC
November 2010

Stereoselective synthesis and conformational study of novel 2',3'-Didehydro-2',3'-dideoxy-4'-selenonucleosides.

J Org Chem 2008 Jun 3;73(11):4259-62. Epub 2008 May 3.

Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul, Korea.

Stereoselective synthesis of novel 2',3'-didehydro-2',3'-dideoxy-4'-selenonucleosides (4'-seleno-d4Ns) 4a- c was accomplished via 4'-selenoribofuranosyl pyrimidines 11a- c, as key intermediates. 4'-Selenoribofuranosyl pyrimidines 11a- c were efficiently synthesized from d-ribose or d-gulonic gamma-lactone using a Pummerer-type condensation as a key step. Introduction of 2',3'-double bond was achieved by treating cyclic 2',3'-thiocarbonate with 1,3-dimethyl-2-phenyl-1,3,2-diazaphospholidine.
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http://dx.doi.org/10.1021/jo8003277DOI Listing
June 2008

Synthesis of 3'-acetamidoadenosine derivatives as potential A3 adenosine receptor agonists.

Nucleosides Nucleotides Nucleic Acids 2008 Apr;27(4):408-20

College of Pharmacy, Seoul National University, Seoul, Korea.

On the basis of high binding affinity of 3'-aminoadenosine derivatives 2b at the human A3 adenosine receptor (AR), 3'-acetamidoadenosine derivatives 3a-e were synthesized from 1,2:5,6-di-O-isopropylidene-D-glucose via stereoselective hydroboration as a key step. Although all synthesized compounds were totally devoid of binding affinity at the human A3AR, our results revealed that 3'-position of adenosine can only be tolerated with small size of a hydrogen bonding donor like hydroxyl or amino group in the binding site of human A3AR.
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http://dx.doi.org/10.1080/15257770801944436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2692331PMC
April 2008

Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-N,N-dialkyluronamides as human A3 adenosine receptor antagonists.

Bioorg Med Chem Lett 2008 Mar 19;18(5):1612-6. Epub 2008 Jan 19.

Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.

On the basis of potent and selective A(3) adenosine receptor (AR) antagonist, 2-chloro-N(6)-(3-iodobenzyl)-4'-thioadenosine-5'-N,N-dimethyluronamide, structure-activity relationships were studied for a series of 5'-N,N-dialkyluronamide derivatives, synthesized from D-gulonic gamma-lactone. From this study, it was revealed that removal of the hydrogen bond-donating ability of the 5'-uronamide was essential for the pure A(3)AR antagonism. 5'-N,N-Dimethyluronamide derivatives exhibited higher binding affinity than larger 5'-N,N-dialkyl or 5'-N,N-cycloalkylamide derivatives, indicating that steric factors are crucial in binding to the human A(3)AR. A N(6)-(3-bromobenzyl) derivative 6c (K(i)=9.32 nM) exhibited the highest binding affinity at the human A(3)AR with very low binding affinities to other AR subtypes.
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http://dx.doi.org/10.1016/j.bmcl.2008.01.070DOI Listing
March 2008

First synthesis of 4'-selenonucleosides showing unusual Southern conformation.

Org Lett 2008 Jan 19;10(2):209-12. Epub 2007 Dec 19.

Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.

The first synthesis of 4'-selenonucleosides was achieved using a Pummerer-type condensation as a key step. All stereoelectronic effects shown in 4'-oxonucleosides were overwhelmed by the size of selenium and steric interactions, driving the conformation to the C2'-endo/ C3'-exo twist (Southern) conformation.
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http://dx.doi.org/10.1021/ol7025558DOI Listing
January 2008

Stereoselective synthesis of homo-apioneplanocin A as potential inhibitor of S-adenosylhomocysteine hydrolase.

Nucleosides Nucleotides Nucleic Acids 2007 ;26(6-7):729-32

College of Pharmacy, Seoul National University, Seoul, Korea.

Homo-apioneplanocin A (1) as a potential inhibitor of S-adenosylhomocysteine hydrolase was synthesized from D-ribose, employing stereoselective hydroxymethylation, regioselective oxidation, and regio- and chemoselective hydroboration as key steps.
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http://dx.doi.org/10.1080/15257770701493559DOI Listing
February 2008

Synthesis and anti-HCV activity Of 2''-beta-hydroxymethylated nucleosides.

Nucleosides Nucleotides Nucleic Acids 2007 ;26(6-7):725-8

College of Pharmacy, Ewha Womans University, Seoul, Korea.

Synthesis of 2' -beta-hydroxymethyl nucleosides 3-6 was accomplished, using stereoselective hydroxymethylation as a key step. Adenine nucleoside 3 showed potent anti-HCV activity, implying that 2' -beta-hydroxymethyl group has the appropriate electronic properties interfering with HCV polymerase.
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http://dx.doi.org/10.1080/15257770701493310DOI Listing
February 2008

Asymmetric synthesis of novel apio carbocyclic nucleoside analogues as potential antiviral and antitumor agent.

Nucleosides Nucleotides Nucleic Acids 2007 ;26(6-7):721-4

College of Pharmacy, Ewha Womans University, Seoul, Korea.

Novel apio carbocyclic nucleosides 18-21 were asymmetrically synthesized as potential antiviral and antitumor agent, starting from D-ribose employing aldol reaction, RCM reaction and Mitsunobu reaction as key reactions.
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http://dx.doi.org/10.1080/15257770701493237DOI Listing
February 2008

Synthesis of N6-substituted 3'-ureidoadenosine derivatives as highly potent agonists at the mutant A3 adenosine receptor.

Nucleosides Nucleotides Nucleic Acids 2007 ;26(6-7):717-9

College of Pharmacy, Ewha Womans University, Seoul, Korea.

Several N6-substituted 3 '-ureidoadenosine derivatives were efficiently synthesized starting from D-glucose for the development of H272E mutant A3 adenosine receptor (AR) agonists. Among compounds tested, 3 '-ureido-N6-(3-iodobenzyl)adenosine (2c) exhibited the highest binding affinity (Ki = 0.22 micro M) at the H272E mutant A3 AR without binding to the natural A3AR.
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http://dx.doi.org/10.1080/15257770701493161DOI Listing
February 2008

Design, synthesis, and anti-tumor activity of 4'-thionucleosides as potent and selective agonists at the human A3 adenosine receptor.

Nucleosides Nucleotides Nucleic Acids 2007 ;26(10-12):1565-8

College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.

On the basis of potent and selective binding affinity of Cl-IB-MECA to the human A(3) adenosine receptor, its 4'-thioadenosine derivatives were efficiently synthesized starting from D-gulonic gamma-lactone. Among compounds tested, 2-chloro-N(6)-(3-iodobenzyl)- and 2-chloro-N(6)-methyl-4' -thioadenosine-5' -methyluronamides (7a and 7b) exhibited nanomolar range of binding affinity (K(i) = 0.38 nM and 0.28 nM, respectively) at the human A(3)AR. These compounds showed anti-growth effects on HL-60 leukemia cell, which resulted from the inhibition of Wnt signaling pathway.
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http://dx.doi.org/10.1080/15257770701547107DOI Listing
March 2008

Asymmetric synthesis of cyclopropyl-fused 2'-C-methylcarbanucleosides as potential anti-HCV agents.

Nucleosides Nucleotides Nucleic Acids 2007 ;26(8-9):1021-4

College of Pharmacy, Ewha Womans University, Seoul, Korea.

Novel 2'-C-methyl-cyclopropyl-fused carbocyclic nucleosides as potential anti-HCV agents were stereoselectively synthesized, utilizing regioselective cleavage of the isopropylidene group and cyclic sulfate chemistry as key steps.
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http://dx.doi.org/10.1080/15257770701508612DOI Listing
March 2008

Stereoselective synthesis of 1'-functionalized-4'-thionucleosides.

Nucleosides Nucleotides Nucleic Acids 2007 ;26(8-9):1011-4

College of Pharmacy, Ewha Womans University, Seoul, Korea.

Stereoselective functionalization of the 1'-position of 4'-thionucleosides was achieved using a stereoselective S(N)2 reaction controlled by 5-membered ring coordination.
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http://dx.doi.org/10.1080/15257770701508588DOI Listing
March 2008

Design, synthesis, and molecular modeling studies of 5'-deoxy-5'-ureidoadenosine: 5'-ureido group as multiple hydrogen bonding donor in the active site of S-adenosylhomocysteine hydrolase.

Bioorg Med Chem Lett 2007 Aug 8;17(16):4456-9. Epub 2007 Jun 8.

Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.

5'-Deoxy-5'-ureidoadenosine was designed and synthesized as a potent inhibitor of S-adenosylhomocysteine hydrolase (SAH), in which 5'-ureido group acted as multiple hydrogen bonding donor in binding with active site residues of SAH in the molecular modeling study.
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http://dx.doi.org/10.1016/j.bmcl.2007.06.013DOI Listing
August 2007

Discovery of a new nucleoside template for human A3 adenosine receptor ligands: D-4'-thioadenosine derivatives without 4'-hydroxymethyl group as highly potent and selective antagonists.

J Med Chem 2007 Jul 8;50(14):3159-62. Epub 2007 Jun 8.

Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.

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), N6-substituted purine analogues bound potently and selectively and acted as antagonists in a cyclic AMP functional assay. An N6-(3-chlorobenzyl)purine analogue 9b displayed a Ki value of 1.66 nM at the human A3 AR. Thus, truncated D-4'-thioadenosine is an excellent template for the design of novel A3 AR antagonists to act at both human and murine species.
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http://dx.doi.org/10.1021/jm070259tDOI Listing
July 2007
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