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Open Access Research article

Di-, tri- and tetra-5'-O-phosphorothioadenosyl substituted polyols as inhibitors of Fhit: Importance of the α-β bridging oxygen and β phosphorus replacement

James M Varnum1, Janina Baraniak2, Renata Kaczmarek2, Wojciech J Stec2 and Charles Brenner1*

Author Affiliations

1 Structural Biology & Bioinformatics Program, Kimmel Cancer Center, Philadelphia, USA

2 Department of Bioorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Lodz, Poland

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BMC Chemical Biology 2001, 1:3  doi:10.1186/1472-6769-1-3

Published: 16 October 2001

Abstract

Background

The human FHIT gene is inactivated early in the development of many human cancers and loss of Fhit in mouse predisposes to cancer while reintroduction of FHIT suppresses tumor formation via induction of apoptosis. Fhit protein, a diadenosine polyphosphate hydrolase, does not require hydrolase activity to function in tumor suppression and may signal for apoptosis as an enzyme-substrate complex. Thus, high affinity nonhydrolyzable substrate analogs may either promote or antagonize Fhit function, depending on their features, in Fhit + cells. Previously synthesized analogs with phosphorothioadenosyl substitutions and "supercharged" branches do not bind better than natural substrates and thus have limited potential as cellular probes.

Results

Here we link adenosine 5'-O-phosphates and phosphorothioates to short-chain polyols to generate a series of substrate analogs. We obtain structure-activity data in the form of in vitro Fhit inhibition for four types of analog substitutions and describe two compounds, inhibitory constants for which are 65 and 75-fold lower than natural substrates.

Conclusions

The best Fhit inhibitors obtained to date separate two or more 5'-O-phosphoromonothioadenosyl moieties with as many bond lengths as in AppppA, maintain oxygen at the location of the α-β bridging oxygen, and replace carbon for the β phosphorus.