European journal of organic chemistry issue:15 pages:2911-2918
Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) has recently been introduced as a potential target for the structure-based design of anti-tuberculosis drugs. Based on the TMPKmt X-ray structure and previous S.A.R. studies, we synthesised the nucleoside analogues 3a-b, 6a-b, 7a-b, and 8a-b, modified in 2'- and T-position of the ribofuranose ring moiety. To our surprise, these analogues showed only moderate binding affinity (i.e. K-i between 118 and 1260 pm). This prompted us to investigate the conformational features of these nucleosides. We concluded that compounds of this series, especially 8a-b, are strongly biased towards the "Northern" furanose ring conformation, whereas X-ray crystallography reveals a preference of TMPKmt for the opposite "Southern" conformers. This paper covers the synthesis, biological evaluation and conformational features (i.e. preferred ring puckering) of the 2'- and T-modified dT analogues. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).