Synthesis and antiviral evaluation of 6'-substituted aristeromycins: potential mechanism-based inhibitors of S-adenosylhomocysteine hydrolase

Abstract

New carbocyclic adenosine analogues substituted at the 6'-position with fluorine, hydroxyl, methylene, or hydroxymethyl have been synthesized as potential mechanism-based inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase. The synthetic routes began with a functionalized (+/-)-azidocyclopentane 2, which was elaborated to the adenosine analogue, or with functionalized cyclopentane epoxides 11, 20, and 27, which were opened directly with adenine in the presence of base. The 6' alpha-fluoro, 6' beta-fluoro, and 6'-methylene carbocyclic adenosine analogues were potent inhibitors of AdoHcy hydrolase. None of the compounds displayed significant activity against herpes simplex virus type 1 or type 2, but several demonstrated potent inhibition of vaccinia virus replication.

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).…”

“…Various attempts have been made to prepare type II mechanism-based inhibitors of this enzyme (14,15,19,21), which would be activated by the enzyme's catalytic activity and inactivate the enzyme through covalent modification. This type of mechanism-based inhibitor, starting with relatively unreactive structures that are activated only by specific targeted enzymes, often have better pharmacological specificity (29).…”

Synthesis and applications of fluorinated nucleoside analogues

“…Prisbe and coworkers [24] have synthesized and biologically evaluated 6 0 -fluorinated aristeromycin 33 and 36 (Scheme 7). Aristeromycin (Fig.…”

“…The sequence of deisopropylidenation, epoxidation, sodium azide ring opening and re-isopropylidenation gave azide 31 and its isomer. Using the same strategy as that described by Prisbe [24] the target nucleoside 33 was obtained. Jeong's group have synthesized fluoroneplanocin A 43 [26] and found that it exhibited more potent SAH inhibitory activity than neplanocin A.…”

Recent advances in the synthesis of fluorinated nucleosides

“…Subjecting 491 to the sequence of deisopropylidenation, epoxidation, sodium azide ring opening and re-isopropylidenation gave the azide 485 along with its isomer. Using the same procedure as that described by Prisbe et al,228 the target nucleoside 6 0 b-fluoroaristeromycin 487 was provided. As an extension of their work, the 5 0 -noraristeromycin fluoro analogue 492 and its enantiomer 493 were also synthesized from 272 in view of the fact that 5 0 -noraristeromycin has been a source of new antiviral candidates.…”