Flavones such as chrysin show structural similarities to androgens, the substrates of human aromatase, which converts androgens to estrogens. Aromatase is a key target in the treatment of hormone-dependent tumors, including breast cancer. Flavone-based aromatase inhibitors are of growing interest, and chrysin in particular provides a (natural) lead structure. This paper reports multicomponent synthesis as a means for facile modification of the chrysin core structure in order to add functional elements. A Mannich-type reaction was used to synthesize a range of mono-and disubstituted chrysin derivatives, some of which are more effective aromatase inhibitors than the benchmark compound, aminoglutethimide. Similarly, the reaction of chrysin with various isonitriles and acetylene dicarboxylates results in a new class of flavone derivatives, tricyclic pyrano-flavones which also inhibit human aromatase. Multicomponent reactions involving flavones therefore enable the synthesis of a variety of derivatives, some of which may be useful as anticancer agents.
2-exo-Methyl-5,7-dichloronorbornane-2-endo-carboxamide (XXXIX).-The dichloro acid (22.0 g.) was refluxed for 3 hr. with 75 ml. of thionyl chloride and distilled through a short Vigreux column. The colorless acid chloride (21.6 g., 90%, b.p. 84-87°(0.03 mm.)) which crystallized as hard rosettes upon standing, was dissolved in 250 ml. of absolute ether. Gaseous ammonia was passed over the surface of the stirred solution for 1 hr. with ice-cooling. The suspension was allowed to stand overnight at room temperature, evaporated to dryness and the residue was washed well with water. The coarse crystalline product (19.5 g., 89%, m.p. 152-156°) was recrystallized twice from toluene to yield 15.8 g., m.p. 160-161°.
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