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

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

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 IC50s of 13 and 5nM, respectively. Folate didemnin B was...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (1), p.709-712
Hauptverfasser: Henne, Walter A., Kularatne, Sumith A., Ayala-López, Wilfredo, Doorneweerd, Derek D., Stinnette, Torian W., Lu, Yingjuan, Low, Philip S.
Format: Artikel
Sprache:eng
Schlagworte:
Animals
Biological and medical sciences
Carbon - chemistry
cytotoxicity
Depsipeptides - chemical synthesis
Depsipeptides - pharmacology
Dose-Response Relationship, Drug
Folate
Folate didemnin B
Folate receptor
folic acid
Folic Acid - chemistry
hydrophilicity
Hydrophobic and Hydrophilic Interactions
Inflammation
Inflammation - drug therapy
Inhibitory Concentration 50
Macrophage
Macrophages - cytology
Medical sciences
Mice
Models, Biological
Models, Chemical
Peptides - chemistry
Pharmacology. Drug treatments
Prodrugs - pharmacology
tumor necrosis factor-alpha
Tumor Necrosis Factor-alpha - metabolism
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Beschreibung
Zusammenfassung: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 IC50s of 13 and 5nM, 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.10.042