title: 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.
authors.affiliation: Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA. whenne@govst.edu
authors.forename: Walter A
authors.initials: WA
authors.lastname: Henne
authors.forename: Sumith A
authors.initials: SA
authors.lastname: Kularatne
authors.forename: Wilfredo
authors.initials: W
authors.lastname: Ayala-López
authors.forename: Derek D
authors.initials: DD
authors.lastname: Doorneweerd
authors.forename: Torian W
authors.initials: TW
authors.lastname: Stinnette
authors.forename: Yingjuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Philip S
authors.initials: PS
authors.lastname: Low
mesh_terms: D000818:Animals; D002244:Carbon / Q000737:chemistry; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005492:Folic Acid / Q000737:chemistry*; D057927:Hydrophobic and Hydrophilic Interactions; D007249:Inflammation / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008954:Models, Biological; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry; D011355:Prodrugs / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D047630:Depsipeptides; D010455:Peptides; D011355:Prodrugs; D014409:Tumor Necrosis Factor-alpha; C030051:didemnins; D002244:Carbon; D005492:Folic Acid