Podophyllotoxin analogues active versus Trypanosoma brucei

Md Jashim Uddin; David C. Smithson; Kristin M. Brown; Brenda C. Crews; Michele Connelly; Fangyi Zhu; Lawrence J. Marnett; R. Kiplin Guy

doi:10.1016/j.bmcl.2010.01.009

Podophyllotoxin analogues active versus Trypanosoma brucei

Md Jashim Uddin, David C. Smithson, Kristin M. Brown, Brenda C. Crews, Michele Connelly, Fangyi Zhu, Lawrence J. Marnett, R. Kiplin Guy

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

8 Scopus citations

Abstract

In an effort to discover novel anti-trypanosomal compounds, a series of podophyllotoxin analogues coupled to non-steroidal anti-inflammatory drugs (NSAIDs) has been synthesized and evaluated for activity versus Trypanosoma brucei and a panel of human cell lines, revealing compounds with low nano-molar potencies. It was discovered that coupling of NSAIDs to podophyllotoxin increased the potencies of both compounds over 1300-fold. The compounds were shown to be cytostatic in nature and seem to act via de-polymerization of tubulin in a manner consistent with the known activities of podophyllotoxin. The potencies against T. brucei correlated directly with Log P values of the compounds, suggesting that the conjugates are acting as hydrophobic tags allowing podophyllotoxin to enter the cell.

Original language	English
Pages (from-to)	1787-1791
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	5
DOIs	https://doi.org/10.1016/j.bmcl.2010.01.009
State	Published - Mar 1 2010

Bibliographical note

Funding Information:
We acknowledge support by the American Lebanese Syrian Associated Charities (ALSAC), St. Jude Children’s Research Hospital, and NIH Grant IU54CA105296 . We thank Dr. J. Pietenpol for the primary human mammary epithelial cells.

Funding

We acknowledge support by the American Lebanese Syrian Associated Charities (ALSAC), St. Jude Children’s Research Hospital, and NIH Grant IU54CA105296 . We thank Dr. J. Pietenpol for the primary human mammary epithelial cells.

Funders	Funder number
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	U54CA105296
St. Jude Children's Research Hospital
American Lebanese Syrian Associated Charities

Keywords

Microtubule
Sleeping sickness
Trypanosoma brucei

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.bmcl.2010.01.009

Cite this

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title = "Podophyllotoxin analogues active versus Trypanosoma brucei",

abstract = "In an effort to discover novel anti-trypanosomal compounds, a series of podophyllotoxin analogues coupled to non-steroidal anti-inflammatory drugs (NSAIDs) has been synthesized and evaluated for activity versus Trypanosoma brucei and a panel of human cell lines, revealing compounds with low nano-molar potencies. It was discovered that coupling of NSAIDs to podophyllotoxin increased the potencies of both compounds over 1300-fold. The compounds were shown to be cytostatic in nature and seem to act via de-polymerization of tubulin in a manner consistent with the known activities of podophyllotoxin. The potencies against T. brucei correlated directly with Log P values of the compounds, suggesting that the conjugates are acting as hydrophobic tags allowing podophyllotoxin to enter the cell.",

keywords = "Microtubule, Sleeping sickness, Trypanosoma brucei",

author = "Uddin, \{Md Jashim\} and Smithson, \{David C.\} and Brown, \{Kristin M.\} and Crews, \{Brenda C.\} and Michele Connelly and Fangyi Zhu and Marnett, \{Lawrence J.\} and Guy, \{R. Kiplin\}",

note = "Funding Information: We acknowledge support by the American Lebanese Syrian Associated Charities (ALSAC), St. Jude Children{\textquoteright}s Research Hospital, and NIH Grant IU54CA105296 . We thank Dr. J. Pietenpol for the primary human mammary epithelial cells. ",

year = "2010",

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doi = "10.1016/j.bmcl.2010.01.009",

language = "English",

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AU - Uddin, Md Jashim

AU - Smithson, David C.

AU - Brown, Kristin M.

AU - Crews, Brenda C.

AU - Connelly, Michele

AU - Zhu, Fangyi

AU - Marnett, Lawrence J.

AU - Guy, R. Kiplin

N1 - Funding Information: We acknowledge support by the American Lebanese Syrian Associated Charities (ALSAC), St. Jude Children’s Research Hospital, and NIH Grant IU54CA105296 . We thank Dr. J. Pietenpol for the primary human mammary epithelial cells.

PY - 2010/3/1

Y1 - 2010/3/1

N2 - In an effort to discover novel anti-trypanosomal compounds, a series of podophyllotoxin analogues coupled to non-steroidal anti-inflammatory drugs (NSAIDs) has been synthesized and evaluated for activity versus Trypanosoma brucei and a panel of human cell lines, revealing compounds with low nano-molar potencies. It was discovered that coupling of NSAIDs to podophyllotoxin increased the potencies of both compounds over 1300-fold. The compounds were shown to be cytostatic in nature and seem to act via de-polymerization of tubulin in a manner consistent with the known activities of podophyllotoxin. The potencies against T. brucei correlated directly with Log P values of the compounds, suggesting that the conjugates are acting as hydrophobic tags allowing podophyllotoxin to enter the cell.

AB - In an effort to discover novel anti-trypanosomal compounds, a series of podophyllotoxin analogues coupled to non-steroidal anti-inflammatory drugs (NSAIDs) has been synthesized and evaluated for activity versus Trypanosoma brucei and a panel of human cell lines, revealing compounds with low nano-molar potencies. It was discovered that coupling of NSAIDs to podophyllotoxin increased the potencies of both compounds over 1300-fold. The compounds were shown to be cytostatic in nature and seem to act via de-polymerization of tubulin in a manner consistent with the known activities of podophyllotoxin. The potencies against T. brucei correlated directly with Log P values of the compounds, suggesting that the conjugates are acting as hydrophobic tags allowing podophyllotoxin to enter the cell.

KW - Microtubule

KW - Sleeping sickness

KW - Trypanosoma brucei

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Podophyllotoxin analogues active versus Trypanosoma brucei

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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