SYNTHESIS OF HYDROXYLATED CYCLOHEXENYLADENINES AND CYCLOHEXANYLADENINES AS POTENTIAL INHIBITORS OF S-ADENOSYLHOMOCYSTEINE HYDROLASE

(Dihydroxycyclohexenyl)- and (trihydroxycyclohexenyl)adenines and (dihydroxycyclohexanyl)- and (trihydroxycyclohexanyl)adenines were prepared regio- and diastereoselectively by starting from cis-3,5-cyclohexadiene-1,2-diol and 1,3-cyclohexadiene. Palladium(0) [Pd(0)]-catalyzed addition of adenine to allylic epoxide 6, prepared from cis-1,2-(isopropylidenedioxy)cyclohexa-3,5-diene, afforded a single product which was chemically and spectroscopically identified as the 1,2-cis addition product 9. In contrast, treatment of allylic epoxide 6 with adenine in the absence of a Pd(0) catalyst afforded the trans-1,2-ring-opened product 23. Both 9 and 23 were converted to various di- and trihydroxylated cyclohexenyl- and cyclohexanyladenines. Cyclohexadiene was exploited to obtain related carbocyclic "nucleosides". Monoepoxidation followed by Pd(0)-catalyzed addition of adenine afforded the cis-1,4-addition product 27. OsO4 oxidation following by standard methodology yielded 3 and 4, six-membered ring homologs of carbocyclic nucleosides 1 and 2, previously shown to be selective and potent inhibitors of S-adenosylhomocysteine hydrolase and broad-spectrum antiviral agents. Toward the cyclohexenyladenines, (diethylamino)sulfur trifluoride (DAST) was utilized to effect an unexpected dehydration. All of the hydroxylated cyclohexenyladenine analogs (10, 15, 22, and 24) and hydroxylated cyclohexanyladenine analogs (4, 11, 16, 25, and 28) except analog 3 were shown to be devoid of inhibitory effects against bovine liver S-adenosylhomocysteine (AdoHcy) hydrolase at concentrations up to 10 muM. Analog 3 showed some inhibitor activity of the hydrolase (1 muM, 26.7%; 10 muM, 59.6%), but it was not sufficient to warrant additional biological evaluation.