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

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

Houston Methodist

Research output: Contribution to journal › Article › peer-review

18 Scopus citations

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 ₅₀s 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.

Original language	English (US)
Pages (from-to)	709-712
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	22
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2011.10.042
State	Published - Jan 1 2012

Keywords

Folate
Folate didemnin B
Folate receptor
Inflammation
Macrophage

ASJC Scopus subject areas

Pharmaceutical Science
Drug Discovery
Organic Chemistry
Molecular Medicine
Molecular Biology
Clinical Biochemistry
Biochemistry

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10.1016/j.bmcl.2011.10.042

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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 50s 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.",

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T1 - Synthesis and activity of folate conjugated didemnin B for potential treatment of inflammatory diseases

AU - Henne, Walter A.

AU - Kularatne, Sumith A.

AU - Ayala-López, Wilfredo

AU - Doorneweerd, Derek D.

AU - Stinnette, Torian W.

AU - Lu, Yingjuan

AU - Low, Philip S.

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AB - 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 50s 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.

KW - Folate

KW - Folate didemnin B

KW - Folate receptor

KW - Inflammation

KW - Macrophage

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

Abstract

Keywords

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