RECENT IMPROVEMENTS TOWARDS THE SYNTHESIS OF THE C-GLUCURONOSYL CANCER CHEMOPREVENTIVE (β-d-GLUCOPYRANOSYLURONATE)-4-RETINAMIDOPHENYLMETHANE

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Abstract
Evidence suggests that the glucuronide conjugates of retinoids may be active metabolites of the parent compounds with potential utility as drugs.1 We have recently shown that the O-glucuronide metabolite 1 of the synthetic retinoid N-4-hydroxyphenylretinamide (2) shows reduced toxicity and a significant chemopreventive advantage relative to the parent retinoid in a carcinogen-induced rat mammary cancer model.2 In efforts to determine whether these conjugates function as intact molecules or must be hydrolyzed back to 2, we designed and synthesized a series of C-glycosyl and C-glucuronosyl analogues of 1 3. Our syntheses of these compounds are lengthy (10-12 steps) and lead to the desired products in less than 4% overall yields. Limitations on the availability of these compounds led us to evaluate them using a modified protocol for the carcinogen-induced rat mammary tumor model. While many of our analogues showed cancer chemopreventive activity in this assay, C-glucuronosyl analogue 3 has proven to be the most effective analogue of 2 we have yet evaluated in this model.4 Unfortunately, compound 3 was prepared in the poorest overall yield among these analogues. However, its potent activity and low toxicity make it an important candidate for expanded biological studies. Because additional studies of this important new compound will benefit from improvements in its synthesis, we briefly describe below recent dramatic improvements we have made in the preparation of 3.