Mycobacterium tuberculosis Thymidine Monophosphate Kinase Inhibitors: Biological Evaluation and Conformational Analysis of 2′- and 3′-Modified Thymidine Analogues

✍ Scribed by Philippe Van Rompaey; Koen Nauwelaerts; Veerle Vanheusden; Jef Rozenski; Hélène Munier-Lehmann; Piet Herdewijn; Serge Van Calenbergh

• Publisher: John Wiley and Sons
• Year: 2003
• Tongue: English
• Weight: 170 KB
• Volume: 2003
• Category: Article
• ISSN: 1434-193X
• DOI: 10.1002/ejoc.200300177

✦ Synopsis

Abstract

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 3′‐position of the ribofuranose ring moiety. To our surprise, these analogues showed only moderate binding affinity (i.e. K~i~ between 118 and 1260 μM). 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 3′‐modified dT analogues. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)