S. Hou et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1667–1669
1669
test these nucleotide analogs against the human mitochondrial
NAD(P)+-dependent ME in the future.
blank
6a
6b
6c
6d
6e
6f
In summary, we developed an efficient, four-step synthetic
strategy for preparation of nucleotide analogs contained the 1,2,3-
triazole moiety starting form tetra-O-acetylribose in 55–63% total
yields. Similar strategy should be applicable for medicinal chemists
to quickly assemble a large number of biologically active nucleotide
derivatives. We are currently synthesizing more complex mole-
cules using those analogs as the building blocks.
6g
6h
6i
Supplementary data
Supplementary data associated with this article can be found, in
6j
6k
References and notes
0
10 20 30 40 50 60 70 80 90 100 110
Relative rate (%)
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To test the biological activity of nucleotide analogs 6a–6k, we
evaluated their inhibitory effects against the recombinant E. coli
NAD-ME.24 Most of the compounds showed some inhibition on this
enzyme. Among them, 6b showed the strongest inhibition (Fig. 1).
Detailed inhibition kinetics indicated that 6b acted with respect to
NAD as a linear mixed inhibitor with a Ki value of 0.057 mM
(Fig. 2). Early data showed that ATP had a competitive-inhibition
to human mitochondrial NAD(P)+-dependent ME, and the Ki value
was 0.081 mM with respect to NAD.35 Thus, these triazole moiety-
containing nucleotide analogs were close to ATP in terms of inhibi-
tion on ME. Because the ME from E. coli shares high sequence
identity with that of the human enzyme, it will be interesting to