Doubly homologated dihalovinyl and acetylene analogues of adenosine: synthesis, interaction with S-adenosyl-L-homocysteine hydrolase, and antiviral and cytostatic effects.
Treatment of the 6-aldehyde derived by Moffatt oxidation of 3-O-benzoyl-1,2-O-isopropylidene-alpha-D-ribo-hexofuranose (2c) with the dibromo- or bromofluoromethylene Wittig reagents generated in situ with tetrabromomethane or tribromofluoromethane, triphenylphosphine, and zinc gave the dihalomethyleneheptofuranose analogues 3b and 3d, respectively. Acetolysis, coupling with adenine, and deprotection gave 9-(7,7-dibromo-5,6, 7-trideoxy-beta-D-ribo-hept-6-enofuranosyl)adenine (5a) or its bromofluoro analogue 5b. Treatment of 5a with excess butyllithium provided the acetylenic derivative 9-(5,6, 7-trideoxy-beta-D-ribo-hept-6-ynofuranosyl)adenine (6). The doubly homologated vinyl halides 5a and 5b and acetylenic 6 adenine nucleosides were designed as putative substrates of the "hydrolytic activity" of S-adenosyl-L-homocysteine (AdoHcy) hydrolase. Incubation of AdoHcy hydrolase with 5a, 5b, and 6 resulted in time- and concentration-dependent inactivation of the enzyme (K(i): 8.5 +/- 0.5, 17 +/- 2, and 8.6 +/- 0.5 microM, respectively), as well as partial reduction of enzyme-bound NAD(+) to E-NADH. However, no products of the "hydrolytic activity" were observed indicating these compounds are type I mechanism-based inhibitors. The compounds displayed minimal antiviral and cytostatic activity, except for 6, against vaccinia virus and vesicular stomatitis virus (IC(50): 15 and 7 microM, respectively). These viruses typically fall within the activity spectrum of AdoHcy hydrolase inhibitors.
Wnuk
S F
SF
Department of Chemistry, Florida International University, Miami, Florida 33199, USA. wnuk@fiu.edu
Valdez
C A
CA
Khan
J
J
Moutinho
P
P
Robins
M J
MJ
Yang
X
X
Borchardt
R T
RT
Balzarini
J
J
De Clercq
E
E
D043383:Adenosylhomocysteinase; D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016048:Dideoxyadenosine / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D010920:Placenta / Q000737:chemistry; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000480:Alkynes; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D016048:Dideoxyadenosine; D006867:Hydrolases; D043383:Adenosylhomocysteinase