The Her-2/
Neu receptor tyrosine kinase is vastly overexpressed in about 30% of primary breast, ovary, and gastric
carcinomas. The nakijiquinones are the only naturally occurring inhibitors of this important oncogene, and structural analogues of the nakijiquinones may display inhibitory properties toward other
receptor tyrosine kinases involved in cell signaling and proliferation. Here, we describe the first enantioselective synthesis of the nakijiquinones. Key elements of the synthesis are (i) the reductive alkylation of a Wieland-Miescher-type enone with a tetramethoxyaryl
bromide, (ii) the oxidative conversion of the aryl ring into a p-quinoid system, (iii) the regioselective 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 corresponding vinylogous
amide. The correct stereochemistry and substitution patterns are completed by conversion of two keto groups into a methyl group and an endocyclic
olefin via olefination/reduction and olefination/isomerization sequences, respectively. This synthesis route also gave access to analogues of
nakijiquinone C with inverted configuration at C-2 or with an exocyclic instead of an endocyclic double bond. Investigation of the
kinase-inhibiting properties of the synthesized derivatives revealed that the C-2 epimer 30 of
nakijiquinone C is a potent and selective inhibitor of the KDR receptor, a
receptor tyrosine kinase involved in
tumor angiogenesis. Molecular modeling 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 into the structural basis for the difference in activity between the
natural product nakijiquinone C and the C-2 epimer 30.