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3'-C-branched-chain-substituted nucleosides and nucleotides as potent inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase

Veerle Vanheusden, Hélène Munier-Lehmann, Matheus Froeyen, Laurence Dugué, Arne Heyerick UGent, Denis De Keukeleire UGent, Sylvie Pochet, Roger Busson, Piet Herdewijn and Serge Van Calenbergh UGent (2003) JOURNAL OF MEDICINAL CHEMISTRY. 46(18). p.3811-3821
abstract
Thymidine monophosphate kinase (TMPK) of Mycobacterium tuberculosis (TMPKmt) represents an attractive target for blocking the bacterial DNA synthesis. In an attempt to find high-affinity inhibitors of TMPKmt, a cavity in the enzyme at the X-position was explored via the introduction of various substituents at the X-position of the thymidine monophosphate (dTMP) scaffold. Various 3'-C-branched chain substituted nucleotides in the 2'-deoxyribo (3-6) and ribo series (7, 8) were synthesized from one key intermediate (23). 2'-Deoxy analogues proved to be potent inhibitors of TMPKmt: 3'-CH(2)NH(2) (4), 3'-CH(2)N(3) (3), and 3'-CH(2)F (5) nucleotides exhibit the highest affinities within this series, with K(i) values of 10.5, 12, and 15 muM, respectively. These results show that TMPKmt tolerates the introduction of sterically demanding substituents at the X-position. Ribo analogues experience a significant affinity decrease, which is probably due to steric hindrance of Tyr103 in close vicinity of the 2'-position. Although the 5'-O-phosphorylated compounds have somewhat higher affinities for the enzyme, the parent nucleosides generally exhibit affinities for TMPKmt in the same order of magnitude and display a superior selectivity profile versus human TMPK. This series of inhibitors holds promise for the development of a new class of antituberculosis agents.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
GENETIC ALGORITHM, HUMAN THYMIDYLATE KINASE, AZT ACTIVATION, ANALOGS, PURIFICATION, RESOLUTION
journal title
JOURNAL OF MEDICINAL CHEMISTRY
J. Med. Chem.
volume
46
issue
18
pages
3811 - 3821
Web of Science type
Article
Web of Science id
000184942500008
JCR category
CHEMISTRY, MEDICINAL
JCR impact factor
4.82 (2003)
JCR rank
3/35 (2003)
JCR quartile
1 (2003)
ISSN
0022-2623
DOI
10.1021/jm021108n
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
209651
handle
http://hdl.handle.net/1854/LU-209651
date created
2004-04-07 16:54:00
date last changed
2014-11-07 14:30:42
@article{209651,
  abstract     = {Thymidine monophosphate kinase (TMPK) of Mycobacterium tuberculosis (TMPKmt) represents an attractive target for blocking the bacterial DNA synthesis. In an attempt to find high-affinity inhibitors of TMPKmt, a cavity in the enzyme at the X-position was explored via the introduction of various substituents at the X-position of the thymidine monophosphate (dTMP) scaffold. Various 3'-C-branched chain substituted nucleotides in the 2'-deoxyribo (3-6) and ribo series (7, 8) were synthesized from one key intermediate (23). 2'-Deoxy analogues proved to be potent inhibitors of TMPKmt: 3'-CH(2)NH(2) (4), 3'-CH(2)N(3) (3), and 3'-CH(2)F (5) nucleotides exhibit the highest affinities within this series, with K(i) values of 10.5, 12, and 15 muM, respectively. These results show that TMPKmt tolerates the introduction of sterically demanding substituents at the X-position. Ribo analogues experience a significant affinity decrease, which is probably due to steric hindrance of Tyr103 in close vicinity of the 2'-position. Although the 5'-O-phosphorylated compounds have somewhat higher affinities for the enzyme, the parent nucleosides generally exhibit affinities for TMPKmt in the same order of magnitude and display a superior selectivity profile versus human TMPK. This series of inhibitors holds promise for the development of a new class of antituberculosis agents.},
  author       = {Vanheusden, Veerle and Munier-Lehmann, H{\'e}l{\`e}ne and Froeyen, Matheus and Dugu{\'e}, Laurence and Heyerick, Arne and De Keukeleire, Denis and Pochet, Sylvie and Busson, Roger and Herdewijn, Piet and Van Calenbergh, Serge},
  issn         = {0022-2623},
  journal      = {JOURNAL OF MEDICINAL CHEMISTRY},
  keyword      = {GENETIC ALGORITHM,HUMAN THYMIDYLATE KINASE,AZT ACTIVATION,ANALOGS,PURIFICATION,RESOLUTION},
  language     = {eng},
  number       = {18},
  pages        = {3811--3821},
  title        = {3'-C-branched-chain-substituted nucleosides and nucleotides as potent inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase},
  url          = {http://dx.doi.org/10.1021/jm021108n},
  volume       = {46},
  year         = {2003},
}

Chicago
Vanheusden, Veerle, Hélène Munier-Lehmann, Matheus Froeyen, Laurence Dugué, Arne Heyerick, Denis De Keukeleire, Sylvie Pochet, Roger Busson, Piet Herdewijn, and Serge Van Calenbergh. 2003. “3’-C-branched-chain-substituted Nucleosides and Nucleotides as Potent Inhibitors of Mycobacterium Tuberculosis Thymidine Monophosphate Kinase.” Journal of Medicinal Chemistry 46 (18): 3811–3821.
APA
Vanheusden, Veerle, Munier-Lehmann, H., Froeyen, M., Dugué, L., Heyerick, A., De Keukeleire, D., Pochet, S., et al. (2003). 3’-C-branched-chain-substituted nucleosides and nucleotides as potent inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase. JOURNAL OF MEDICINAL CHEMISTRY, 46(18), 3811–3821.
Vancouver
1.
Vanheusden V, Munier-Lehmann H, Froeyen M, Dugué L, Heyerick A, De Keukeleire D, et al. 3’-C-branched-chain-substituted nucleosides and nucleotides as potent inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase. JOURNAL OF MEDICINAL CHEMISTRY. 2003;46(18):3811–21.
MLA
Vanheusden, Veerle, Hélène Munier-Lehmann, Matheus Froeyen, et al. “3’-C-branched-chain-substituted Nucleosides and Nucleotides as Potent Inhibitors of Mycobacterium Tuberculosis Thymidine Monophosphate Kinase.” JOURNAL OF MEDICINAL CHEMISTRY 46.18 (2003): 3811–3821. Print.