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

Walter A Henne; Sumith A Kularatne; Wilfredo Ayala-López; Derek D Doorneweerd; Torian W Stinnette; Yingjuan Lu; Philip S Low

doi:10.1016/j.bmcl.2011.10.042

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

Bioorg Med Chem Lett. 2012 Jan 1;22(1):709-12. doi: 10.1016/j.bmcl.2011.10.042. Epub 2011 Oct 21.

Authors

Walter A Henne¹, Sumith A Kularatne, Wilfredo Ayala-López, Derek D Doorneweerd, Torian W Stinnette, Yingjuan Lu, Philip S Low

Affiliation

¹ Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN 47907, USA. whenne@govst.edu

PMID: 22100311
DOI: 10.1016/j.bmcl.2011.10.042

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.

Published by Elsevier Ltd.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Carbon / chemistry
Depsipeptides / chemical synthesis*
Depsipeptides / pharmacology*
Dose-Response Relationship, Drug
Folic Acid / chemistry*
Hydrophobic and Hydrophilic Interactions
Inflammation / drug therapy*
Inhibitory Concentration 50
Macrophages / cytology
Mice
Models, Biological
Models, Chemical
Peptides / chemistry
Prodrugs / pharmacology
Tumor Necrosis Factor-alpha / metabolism

Substances

Depsipeptides
Peptides
Prodrugs
Tumor Necrosis Factor-alpha
didemnins
Carbon
Folic Acid