Total synthesis and biological evaluation of the nakijiquinones

The Her-2/Neu receptor tyrosine kinase is vastly overexpressed in about 30% of primary breast, ovary, and gastric carcinomas. The nakijiquinones are t he only naturally occurring inhibitors of this important oncogene, and stru ctural analogues of the nakijiquinones may display inhibitory properties to ward other receptor tyrosine kinases involved in cell signaling and prolife ration. Here, we describe the first enantioselective synthesis of the nakij iquinones. Key elements of the synthesis are (i) the reductive alkylation o f a Wieland-Miescher-type enone with a tetramethoxyaryl bromide, (ii) the o xidative conversion of the aryl ring into a p-quinoid system, (iii) the reg ioselective saponification of one of the two vinylogous esters incorporated therein, and (iv) the selective introduction of different amino acids via nucleophilic conversion of the remaining vinylogous ester into the correspo nding vinylogous amide. The correct stereochemistry and substitution patter ns are completed by conversion of two keto groups into a methyl group and a n endocyclic olefin via olefination/reduction and olefination/isomerization sequences, respectively. This synthesis route also gave access to analogue s of nakijiquinone C with inverted configuration at C-2 or with an exocycli c instead of an endocyclic double bond. Investigation of the kinase-inhibit ing properties of the synthesized derivatives revealed that the C-2 epimer 30 of nakijiquinone C is a potent and selective inhibitor of the KDR recept or, a receptor tyrosine kinase involved in tumor angiogenesis. Molecular mo deling studies based on the crystal structure of KDR and a model of the ATP binding site built from a crystal structure of FGF-R revealed an insight i nto the structural basis for the difference in activity between the natural product nakijiquinone C and the C-2 epimer 30.