Synthesis and activity of folate conjugated didemnin B for potential treatment of inflammatory diseases.

Abstract A folate receptor targeted didemnin B conjugate was synthesized using a hydrophilic peptide spacer linked to folate via a releasable disulfide carbonate linker. Cell cytotoxicity and TNF-α inhibition in RAW264.7 macrophage-like cells exhibited IC 50 s of 13 and 5 nM, respectively. Folate didemnin B was found to be ∼50–100 fold more potent than didemnin B itself. More importantly, activity of the prodrug was blocked by excess folic acid, demonstrating receptor-mediated cellular uptake of the conjugate.