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

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

Access to Document

10.1016/j.bmcl.2011.10.042

Cite this

@article{c45bc81c01234ee780936f13ddd4ac15,

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.",

keywords = "Folate, Folate didemnin B, Folate receptor, Inflammation, Macrophage",

author = "Henne, {Walter A.} and Kularatne, {Sumith A.} and Wilfredo Ayala-L{\'o}pez and Doorneweerd, {Derek D.} and Stinnette, {Torian W.} and Yingjuan Lu and Low, {Philip S.}",

year = "2012",

month = jan,

day = "1",

doi = "10.1016/j.bmcl.2011.10.042",

language = "English (US)",

volume = "22",

pages = "709--712",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Limited",

number = "1",

}

TY - JOUR

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.

PY - 2012/1/1

Y1 - 2012/1/1

N2 - 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.

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

UR - http://www.scopus.com/inward/record.url?scp=84655169611&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84655169611&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2011.10.042

DO - 10.1016/j.bmcl.2011.10.042

M3 - Article

C2 - 22100311

AN - SCOPUS:84655169611

SN - 0960-894X

VL - 22

SP - 709

EP - 712

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 1

ER -

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this