Potential inhibitors of S-adenosylmethionine-dependent methyltransferases. 10. Base- and amino acid modified analogues of S-aristeromycinyl-L-homocysteine

A series of base- and amino acid modified analogues of S-aristeromycinyl-L-homocysteine, a carbocyclic nucleoside, were synthesized and evaluated as inhibitors of S-adenosyl-L-methionine-dependent methyltransferases, including catechol O-methyltransferase, phenylethanolamine N-methyltransferase, and histamine N-methyltransferase. The base-modified analogues (8-azaadenine, 3-deazaadenine, and N6-methyladenine) were prepared by reaction of the corresponding carbocyclic 5'-chloro-5'-deoxynucleosides with the anion of homocysteine generated in situ either from L-homocystine or S-benzyl-L-homocysteine in Na/liquid NH3 or with DL-homocysteine thiolactone in alkaline solution. S-Aristeromycinyl-D-homocysteine was prepared with use of D-homocystine in the Na/liquid NH3 reaction. The sulfoxide and sulfone analogues were prepared by oxidation of S-aristeromycinyl-L-homocysteine. The various base- and amino acid modified analogues of S-aristeromycinyl-L-homocysteine were inactive as inhibitors of catechol O-methyltransferase. In contrast, the 3-deaza analogue was a good inhibitor (Ki = 20.5 +/- 1 microM) of phenylethanolamine N-methyltransferase whereas S-aristeromycinyl-D-homocysteine was an excellent inhibitor (Ki = 10.4 +/- 2.4 microM) of histamine N-methyltransferase. On the basis of these results, it would appear that the structural requirements for the binding S-aristeromycinyl-L-homocysteine are similar to those for binding S-adenosyl-L-homocysteine. Therefore, these carbocyclic analogues have the potential of being better inhibitors in vivo, because they should be more stable to metabolism than the ribosyl analogues.