Synthesis of succinimidoalkylbenzaldehyde analogues: Potential bifunctional linkers for bioconjugation

A series of novel 4-substituted benzaldehydes containing a succinimide moiety were synthesized as potential bifunctional linkers for the purpose of binding therapeutic drugs to antibodies raised against cancer cells. These potential benzaldehyde linkers varied in the nature of the para functionality so as to provide a range of potential acid labilities. Synthesis of the linkers involved a Williamson ether formation to make the ether linker 1, a Sonagoshira palladium-catalyzed coupling to synthesize the skeleton of the alkyl linker 2, and formation of an amide bond directly from a methyl ester gave the 4-substituted amide linker 3. As an example of the type of acetal that can be produced using these linkers, uridine was used as an analogue of the cytotoxic compound 5-fluorouridine to give the cyclic acetals 19-21.