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

Producción científica: Article › revisión exhaustiva

8 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	1787-1791
Número de páginas	5
Publicación	Bioorganic and Medicinal Chemistry Letters
Volumen	20
N.º	5
DOI	https://doi.org/10.1016/j.bmcl.2010.01.009
Estado	Published - mar 1 2010

Nota bibliográfica

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.

Financiación

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.

Financiadores	Número del financiador
National Institutes of Health (NIH)
National Childhood Cancer Registry – National Cancer Institute	U54CA105296
St. Jude Children's Research Hospital
American Lebanese Syrian Associated Charities

ODS de las Naciones Unidas

Este resultado contribuye a los siguientes Objetivos de Desarrollo Sostenible

Good health and well being

ASJC Scopus subject areas

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

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10.1016/j.bmcl.2010.01.009

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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",

volume = "20",

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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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DO - 10.1016/j.bmcl.2010.01.009

M3 - Article

C2 - 20129783

AN - SCOPUS:76649095637

SN - 0960-894X

VL - 20

SP - 1787

EP - 1791

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 5

ER -

Podophyllotoxin analogues active versus Trypanosoma brucei

Resumen

Nota bibliográfica

Financiación

ODS de las Naciones Unidas

ASJC Scopus subject areas

Acceder al documento

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Huella

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