Anticancer and antiviral effects and inactivation of S-adenosyl-L-homocysteine hydrolase with 5'-carboxaldehydes and oximes synthesized from adenosine and sugar-modified analogues

Journal of Medicinal Chemistry
S F WnukM J Robins

Abstract

Selectively protected adenine nucleosides were converted into 5'-carboxaldehyde analogues by Moffatt oxidation (dimethyl sulfoxide/dicyclohexylcarbodiimide/dichloroacetic acid) or with the Dess-Martin periodinane reagent. Hydrolysis of a 5'-fluoro-5'-S-methyl-5'-thio (alpha-fluoro thioether) arabinosyl derivative also gave the 5'-carboxaldehyde. Treatment of 5'-carboxaldehydes with hydroxylamine [or O-(methyl, ethyl, and benzyl)hydroxylamine] hydrochloride gave E/Z oximes. Treatment of purified oximes with aqueous trifluoroacetic acid and acetone effected trans-oximation to provide clean samples of 5'-carboxaldehydes. Adenosine (Ado)-5'-carboxaldehyde and its 4'-epimer are potent inhibitors of S-adenosyl-L-homocysteine (AdoHcy) hydrolase. They bind efficiently to the enzyme and undergo oxidation at C3' to give 3'-keto analogues with concomitant reduction of the NAD+ cofactor to give an inactive, tightly bound NADH-enzyme complex (type I cofactor-depletion inhibition). Potent type I inhibition was observed with 5'-carboxaldehydes that contain a ribo cis-2',3'-glycol. Their oxime derivatives are "proinhibitors" that undergo enzyme-catalyzed hydrolysis to release the inhibitors at the active site. The 2'-deoxy and 2'-epimeric (ara...Continue Reading

References

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Citations

Jul 3, 2003·Bioorganic & Medicinal Chemistry·Jennifer A Steere, John F Honek
Mar 24, 2009·The Journal of Organic Chemistry·Manish K Singh, Mahesh K Lakshman
Jun 23, 2007·Nature Reviews. Drug Discovery·Panagiotis A KonstantinopoulosAthanasios G Papavassiliou
Feb 18, 2004·The Journal of Clinical Investigation·Steven Clarke, Fuyuhiko Tamanoi
Oct 11, 2015·Journal of Pharmaceutical Sciences·Katharine Barbara SchowenMichael S Wolfe
Jan 1, 2004·Chemistry & Biology·Eric M BennettSteven E Ealick
Mar 15, 2010·Molecular Informatics·Aliuska M HelgueraM Natália D S Cordeiro
Apr 4, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Brian R LawsonChong Yuan
Nov 24, 2020·Frontiers in Oncology·Carla M Borini EtichettiJavier Girardini
Oct 23, 2020·Acta Pharmacologica Sinica·Wei-Hua WangHong Zhu
Jun 6, 2008·Journal of the American Chemical Society·Fabien BoussicaultChryssostomos Chatgilialoglu

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