期刊
CHEMISTRY & BIODIVERSITY
卷 9, 期 3, 页码 536-556出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbdv.201100285
关键词
Thymidylate synthase; Thymidine monophosphate kinase; Inhibitors; Antimycobacterial activity; 6-Azauracil nucleotides; Nucleotides; Tuberculosis; Mycobacterium tuberculosis
资金
- NATT from European Commission
- Institut Pasteur (GPH Tuberculose, DARRI)
- CNRS
- INSERM
- IWT (Agentschap voor Innovatie door Wetenschap en Technologie)
A series of 5-substituted analogs of 6-aza-2'-deoxyuridine 5'-monophosphate, 6-aza-dUMP, has been synthesized and evaluated as potential inhibitors of the two mycobacterial thymidylate synthases (i.e., a flavin-dependent thymidylate synthase, ThyX, and a classical thymidylate synthase, ThyA). Replacement of C(6) of the natural substrate dUMP by a N-atom in 6-aza-dUMP 1a led to a derivative with weak ThyX inhibitory activity (33% inhibition at 50 mu M). Introduction of alkyl and aryl groups at C(5) of 1a resulted in complete loss of inhibitory activity, whereas the attachment of a 3-(octanamido)prop-1-ynyl side chain in derivative 3 retained the weak level of mycobacterial ThyX inhibition (40% inhibition at 50 mu M). None of the synthesized derivatives displayed any significant inhibitory activity against mycobacterial ThyA. The compounds have also been evaluated as potential inhibitors of mycobacterial thymidine monophosphate kinase (TMPKmt). None of the derivatives showed any significant TMPKmt inhibition. However, replacement of C(6) of the natural substrate (dTMP) by a N-atom furnished 6-aza-dTMP (1b), which still was recognized as a substrate by TMPKmt.
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