ANTICANCER AND ANTIVIRAL EFFECTS AND INACTIVATION OF S-ADENOSYL-L-HOMOCYSTEINE HYDROLASE WITH 5'-CARBOXALDEHYDES AND OXIMES SYNTHESIZED FROM ADENOSINE AND SUGAR-MODIFIED ANALOGS

Selectively protected adenine nucleosides were converted into 5'-carbo xaldehyde analogues by Moffatt oxidation (dimethyl sulfoxide/dicyclohe xylcarbodiimide/dichloroacetic acid) or with the Dess-Martin periodina ne reagent. Hydrolysis of a 5'-fluoro-5'-S-methyl-5'-thio (alpha-fluor o thioether) arabinosyl derivative also gave the 5'-carboxaldehyde. Tr eatment 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 effecte d trans-oximation to provide clean samples of 5'-carboxaldehydes. Aden osine (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 inhibiti on). Potent type I inhibition was observed with 5'-carboxaldehydes tha t contain a ribo cis-2',3'-glycol. Their oxime derivatives are ''proin hibitors'' that undergo enzyme-catalyzed hydrolysis to release the inh ibitors 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 t umor cell lines and was toxic to normal human cells. Analogues had wea ker cytotoxic and antiviral potencies, and the 3'-deoxy compounds were essentially devoid of cytotoxic and antiviral activity.