Anticancer and antiviral effects and inactivation of S-adenosyl-L-homocysteine hydrolase with 5'-carboxaldehydes and oximes synthesized from adenosine and sugar-modified analogues.
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 (arabinosyl) analogues were much weaker inhibitors, and the 3'-deoxy compounds bind very weakly. Ado-5'-carboxaldehyde oxime had potent cytotoxicity in tumor cell lines and was toxic to normal human cells. Analogues had weaker cytotoxic and antiviral potencies, and the 3'-deoxy compounds were essentially devoid of cytotoxic and antiviral activity.
Wnuk
S F
SF
Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602-5700, USA.
Yuan
C S
CS
Borchardt
R T
RT
Balzarini
J
J
De Clercq
E
E
Robins
M J
MJ
D000241:Adenosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry; D043383:Adenosylhomocysteinase; D000447:Aldehydes / Q000138:chemical synthesis*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D000998:Antiviral Agents / Q000138:chemical synthesis*; D002241:Carbohydrates / Q000737:chemistry; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects; D004285:Dogs; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D007939:Leukemia L1210 / Q000188:drug therapy; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D010091:Oximes / Q000138:chemical synthesis*; D014407:Tumor Cells, Cultured; D014616:Vaccinia virus / Q000187:drug effects
C106269:9-(ribo-pentodialdo-1,4-furanosyl)adenine oxime; D000447:Aldehydes; D000970:Antineoplastic Agents; D000998:Antiviral Agents; D002241:Carbohydrates; D004791:Enzyme Inhibitors; D010091:Oximes; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine