6‐Substituted Purines as Inhibitors of 15‐Lipoxygenase; a Structure‐Activity Study

15‐Lipoxygenase (15‐LO) has been implicated in oxidation of low‐density lipoproteins (LDL), a process believed to be important for the development of atherosclerosis, as well as other pathogenic conditions. Potent and selective inhibitors of 15‐LO may have a drug potential. In this study, purines with a variety of substituents have been examined as inhibitors of 15‐lipoxygenase (15‐LO) from soybeans. Several 6‐substitued purines where the purine ring and a phenyl ring in the substituent were separated by a “spacer” were synthesized and their ability to inhibit the enzyme was explored. Sepa ration of the purine and the phenyl rings with none, one or two sp3‐carbons resulted in essentially inactive compounds, trans‐styrylpurines and phenylethynylpurines, on the other hand, they exhibited activity close to the well‐known 15‐LO inhibitor quercetin. High activity was also found when the “spacer” was a trans‐cyclopropyl ring. The shape of the spacer was important; a corresponding cis‐cyclopropylpurine exhibited much less affinity for the enzyme. Only minor differences in inhibitory activity against 15‐LO were found regardless of whether an N‐substituent was situated on N‐9 or N‐7, even when the N‐substituent was relatively large. Also, a variety of substituents in the purine 2‐ and 8‐position were well tolerated.