Unexpected Inhibition of S‐Adenosyl‐L‐homocysteine Hydrolase by a Guanosine Nucleoside.

Abstract

Nucleic acids Nucleic acids U 0700Unexpected Inhibition of S-Adenosyl-L-homocysteine Hydrolase by a Guanosine Nucleoside.-Compound (I) shows a moderate inhibitory activity against S-adenosyl-L-homocysteine hydrolase (SAHase). -(SELEY*, K. L.; QUIRK, S.; SALIM, S.; ZHANG, L.; HAGOS, A.; Bioorg. Med.

Nucleoside Analogs with Fleximer Nucleobase

“…29 There is a scarcity of available information in the literature on the biological targets and established mechanisms of action for fleximer nucleosides. As already pointed out, the distal fleximer guanosine analog 2 (Scheme 1) inhibited the S-adenosyl-L-homocysteine hydrolase, 23 while its triphosphate was an excellent substrate for human fucose-1-phosphate guanylyltransferase (EC 2.7.7.30). 30 Compound 40 activated caspase-3 and caspase-7 (EC 3.4.22.56 and EC 3.4.22.60, respectively), causing apoptosis of cancer cells, while simultaneously acting as agonist of the TLR7 receptor (tolllike receptor 7) that initiates immune response mechanisms.…”

“…22 This could, for example, explain the unexpected earlier observation: fleximer guanosine analog 2 inhibited S-adenosyl-L-homocysteine hydrolase (EC 3.3.1.1) -an enzyme that is specific for adenosine, while fleximer 1 (an adenosine analog) did not interact with this enzyme. 23 Both ribosides and acyclic fleximers 24 predominantly existed in their anti conformations in solutions (compounds 35-38, Fig. 1).…”

Flexible Nucleobase Analogues: Novel Tools for Exploring Nucleic Acids

“…In that regard, the distal guanosine fleximer was observed to inhibit an adenosine-metabolizing enzyme, S-adenosylhomocysteine hydrolase (SAHase) (Seley et al 2003b). It has been speculated that this unexpected inhibition of SAHase is likely due to the existence of an intramolecular H-bond between the 5 0 -hydroxyl and the C2 carbonyl of the base (Fig.…”

Synthetic Routes to a Series of Proximal and Distal 2′-Deoxy Fleximers

“…8 In our own laboratories it was observed that the distal ribofuranose guanosine fleximer, Flex-G 3a (Figure 1) served as an inhibitor of S-adenosylhomocysteine hydrolase (SAHase). 9 This observation is unprecedented, since to our knowledge no other guanosine nucleoside has ever been reported to inhibit SAHase, an adenosine metabolizing enzyme. SAHase is an attractive biological target as it has been implicated in viral and parasitic replication.…”