Synthesis of the Multidrug Reversal Agent Ko143 and Its Parent Natural Product Fumitremorgin C

Ko143 is a tetracyclic, synthetic analog of the fungal metabolite fumitremorgin C. potent and specific inhibitor membrane-bound efflux transporter ABCG2, it reverses ABCG2-mediated drug resistance in cancer cells. Here, we describe an improved synthesis that relies on highly selective, substrate-controlled reduction imine formed Bischler–Napieralski reaction with amide derived from 6-methoxy-l-tryptophan methyl ester isovaleric acid as key step. We have also developed new route to Cbz-l-aspartic ester, m-anisidine differently substituted benzaldehydes. With p-nitrobenzaldehyde one starting materials, this gave access five steps 20 % overall yield; however, less efficient than previously reported 6-methoxy indole.