Investigations into specificity of azepinomycin for inhibition of guanase: discrimination between the natural heterocyclic inhibitor and its synthetic nucleoside analogues.

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Chakraborty S, Shah NH, Fishbein JC, Hosmane RS

Investigations into specificity of azepinomycin for inhibition of guanase: discrimination between the natural heterocyclic inhibitor and its synthetic nucleoside analogues.

Bioorg Med Chem Lett. 2012 Dec 1;22(23):7214-8. doi: 10.1016/j.bmcl.2012.09.053. Epub 2012 Oct 2.

PubMed ID

23084905 [ View in PubMed

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Abstract

In our long and broad program to explore structure-activity relationships of the natural product azepinomycin and its analogues for inhibition of guanase, an important enzyme of purine salvage pathway of nucleic acid metabolism, it became necessary to investigate if the nucleoside analogues of the heterocycle azepinomycin, which are likely to be formed in vivo, would be more or less potent than the parent heterocycle. To this end, we have resynthesized both azepinomycin (1) and its two diastereomeric nucleoside analogues (2 and 3), employing a modified, more efficient procedure, and have biochemically screened all three compounds against a mammalian guanase. Our results indicate that the natural product is at least 200 times more potent toward inhibition of guanase as compared with its nucleoside analogues, with the observed K(i) of azepinomycin (1) against the rabbit liver guanase=2.5 (+/-0.6)x10(-6) M, while K(i) of Compound 2=1.19 (+/-0.02)x10(-4) M and that of Compound 3=1.29 (+/-0.03)x10(-4) M. It is also to be noted that while IC(50) value of azepinomycin against guanase in cell culture has long been reported, no inhibition studies nor K(i) against a pure mammalian enzyme have ever been documented. In addition, we have, for the first time, determined the absolute stereochemistry of the 6-OH group of 2 and 3 using conformational analysis coupled with 2-D (1)H NMR NOESY.

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Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Pentostatin	Adenosine deaminase	Ki (nM)	0	N/A	N/A	Details