Nucleic acid related compounds. 74. Synthesis and biological activity of 2'(and 3')-deoxy-2'(and 3')-methylenenucleoside analogs that function as mechanism-based inhibitors of S-adenosyl-L-homocysteine hydrolase and/or ribonucleotide reductase

Abstract

Treatment of 2-amino-6-chloro-9-(beta-D-ribofuranosyl)purine (21) with TBDMS chloride/imidazole/DMF gave a separable mixture of 5'-O, 2',5'-bis-O (22), 3',5'-bis-O (23), and 2',3',5'-tris-O-TBDMS derivatives. Oxidation of 22 and 23 with CrO3/pyridine/Ac2O, treatment of the respective ketonucleosides with methylenetriphenylphosphorane, and deprotection gave 2-amino-6-chloro-9-[3(and 2)-deoxy-3(and 2)-methylene- beta-D-erythro-pentofuranosyl]purines (28 and 37) that were converted into other 2-amino-6-substituted-purine analogues. Tubercidin was converted into 2'-deoxy-2'-methylenetubercidin (49) by an analogous route. Inactivation of S-adenosyl-L-homocysteine hydrolase by 2'- and 3'-methyleneadenosine analogues was investigated. Mechanism-based inhibition of S-adenosyl-L-homocysteine hydrolase and anticancer and antiviral activities of 2'(and 3')-deoxy-2'(and 3')-methylenenucleoside analogues are discussed.

Overview of Ribonucleotide Reductase Inhibitors: An Appealing Target in Anti-Tumour Therapy

“…CH 2 dNDP shows high resistance to cytidine deaminase (enzyme that degradates nucleotides in excess), which makes it effective against human cancer xenograft models with high levels of cytidine deaminase activity [156], as already tested successfully in vitro and in vivo [157]. Experimental studies revealed that the inhibition involves the formation of a 2'-methyl furanone derivative that presumably inactivates the subunit [158], similarly to 2'-halogenated substrate analogues.…”

A Novel Mechanism-based Inhibitor (6′-Bromo-5′,6′-didehydro-6′-deoxy-6′-fluorohomoadenosine) That Covalently Modifies Human Placental S-Adenosylhomocysteine Hydrolase

“…Michael-type addition of water to this tightly bound intermediate (hydrolytic activity) affords 3Ј-keto-Ado, which is reduced by E⅐NADH to yield Ado and E⅐NAD ϩ . In recent years, significant efforts have been made in designing potent and selective inhibitors of AdoHcy hydrolase (12)(13)(14)(15)(16)(17)(18). Most inhibitors of AdoHcy hydrolase are Ado analogs, which inhibit the enzyme by serving as substrates for the 3Ј-oxidative activity of the enzyme and converting it from the active form (NAD ϩ ) to the inactive form (NADH) (6).…”

The Unabated Synthesis of New Nucleoside Analogues with Antiviral Potential: A Tribute to Morris J. Robins

“…[34,35] The main indication of 3-deazaneplanocin A and related SAH hydrolase inhibitors would be the treatment of such severe hemorrhagic fever virus infections as Ebola. [34,35] Mechanism-based inactivation of SAH hydrolase has been pursued by Morris Robins and his coworkers as a new strategy towards antiviral agents: that is, 2 -deoxy-2 -methylene tubercidin; [36] 6 -(E)-and (Z )-halohomovinyl adenosine derivatives, [37] 5-carboxaldehyde and 5-oximes of adenosine, [38] 4 -haloacetylene adenosine derivatives, [39] and dihalohomovinyl adenosine analogues [40,41] (Figure 7).…”