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Total Synthesis of Arctigenin Derivatives as Potential Anticancer Agents
Published: 28 October 2011 by MDPI in The 15th International Electronic Conference on Synthetic Organic Chemistry session General Organic Synthesis
Abstract: Mitotic spindle dynamics represents an important target of anticancer drugs. Many small natural and semi-synthetic drugs influence tubulin assembly and cause apoptosis of excessively dividing cells. Molecules attacking the colchicine domain of tubulin block its polymerization. Despite this there are colchicine site inhibitors (CSIs) not used in cancer treatment due to their high toxicity, low activity or poor solubility. On the basis of the structure-activity relationships, aryltetralin and dibenzylbutyrolactone lignan-like molecules were designed in an attempt to obtain active drugs. Structure modifications embraced the elimination of typically toxic groups. Two new dibenzylbutyrolactone-type compounds were prepared by total synthesis from substituted benzaldehyde, benzyl bromide and dimethyl succinate. The Stobbe condensation of the substituted benzaldehyde with dimethyl succinate followed with the selective hydrogenation of the double bond and the selective reduction of the ester in the presence of carboxyl led to the β-benzylbutyrolactone. Alkylation of butyrolactone enolate with a substituted benzyl bromide provided the final 2-hydroxy-5\'-methoxy-4\'-O-methyl arctigenin (1) after phenolic group deprotection. The target 2,5\'-dimethoxy-4\'-O-methyl arctigenin (2) was obtained by means of one-step methylation of dibenzylbutyrolactone derivative 1.
Keywords: dibenzylbutyrolactones; microtubule polymerization inhibitors; Stobbe condensation; catalytic hydrogenation; selective reduction