Synthesis and biological evaluation of novel 2-alkoxycarbonylallylester phosphonium derivatives as potential anticancer agents

Zachary S. Gardner; Tanner J. Schumacher; Conor T. Ronayne; Greeshma P. Kumpati; Michael J. Williams; Akira Yoshimura; Hithardha Palle; Chinnadurai Mani; Jon Rumbley; Venkatram R. Mereddy

doi:10.1016/j.bmcl.2021.128136

Synthesis and biological evaluation of novel 2-alkoxycarbonylallylester phosphonium derivatives as potential anticancer agents

Zachary S. Gardner, Tanner J. Schumacher, Conor T. Ronayne, Greeshma P. Kumpati, Michael J. Williams, Akira Yoshimura, Hithardha Palle, Chinnadurai Mani, Jon Rumbley, Venkatram R. Mereddy

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Abstract

Several phosphonium derivatives have been synthesized from Baylis-Hillman (BH) reaction derived allyl bromides and aryl phosphines as mitochondria targeting anticancer agents. In vitro cell proliferation inhibition studies on various solid tumor cell lines indicate that most of the compounds exhibit IC₅₀ values in µM concentrations. Further studies reveal that β-substituted BH bromide derived phosphonium derivatives enhance the biological activity to low µM IC₅₀ values. In vitro metabolic studies show that the lead candidate compound 16 inhibits the production of mitochondrial ATP, increases the proton leak within the mitochondrial membrane and abolishes the spare respiratory capacity in a concentration dependent manner.

Original language	English (US)
Article number	128136
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	45
DOIs	https://doi.org/10.1016/j.bmcl.2021.128136
State	Published - Aug 1 2021

Bibliographical note

Funding Information:
We thank the Department of Chemistry and Biochemistry, University of Minnesota Duluth, College of Pharmacy and Integrated Biosciences, University of Minnesota, Randy Shaver Cancer Research and Community Fund, Whiteside Clinical Research Institute for their financial support.

Publisher Copyright:
© 2021 Elsevier Ltd

Keywords

Anticancer agent
Baylis-Hillman reaction
MTT and SRB assay
MitoStress test
Phosphonium derivatives

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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Gardner, Z. S., Schumacher, T. J., Ronayne, C. T., Kumpati, G. P., Williams, M. J., Yoshimura, A., Palle, H., Mani, C., Rumbley, J., & Mereddy, V. R. (2021). Synthesis and biological evaluation of novel 2-alkoxycarbonylallylester phosphonium derivatives as potential anticancer agents. Bioorganic and Medicinal Chemistry Letters, 45, Article 128136. https://doi.org/10.1016/j.bmcl.2021.128136

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title = "Synthesis and biological evaluation of novel 2-alkoxycarbonylallylester phosphonium derivatives as potential anticancer agents",

abstract = "Several phosphonium derivatives have been synthesized from Baylis-Hillman (BH) reaction derived allyl bromides and aryl phosphines as mitochondria targeting anticancer agents. In vitro cell proliferation inhibition studies on various solid tumor cell lines indicate that most of the compounds exhibit IC50 values in µM concentrations. Further studies reveal that β-substituted BH bromide derived phosphonium derivatives enhance the biological activity to low µM IC50 values. In vitro metabolic studies show that the lead candidate compound 16 inhibits the production of mitochondrial ATP, increases the proton leak within the mitochondrial membrane and abolishes the spare respiratory capacity in a concentration dependent manner.",

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author = "Gardner, {Zachary S.} and Schumacher, {Tanner J.} and Ronayne, {Conor T.} and Kumpati, {Greeshma P.} and Williams, {Michael J.} and Akira Yoshimura and Hithardha Palle and Chinnadurai Mani and Jon Rumbley and Mereddy, {Venkatram R.}",

note = "Funding Information: We thank the Department of Chemistry and Biochemistry, University of Minnesota Duluth, College of Pharmacy and Integrated Biosciences, University of Minnesota, Randy Shaver Cancer Research and Community Fund, Whiteside Clinical Research Institute for their financial support. Publisher Copyright: {\textcopyright} 2021 Elsevier Ltd",

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AU - Gardner, Zachary S.

AU - Schumacher, Tanner J.

AU - Ronayne, Conor T.

AU - Kumpati, Greeshma P.

AU - Williams, Michael J.

AU - Yoshimura, Akira

AU - Palle, Hithardha

AU - Mani, Chinnadurai

AU - Rumbley, Jon

AU - Mereddy, Venkatram R.

N1 - Funding Information: We thank the Department of Chemistry and Biochemistry, University of Minnesota Duluth, College of Pharmacy and Integrated Biosciences, University of Minnesota, Randy Shaver Cancer Research and Community Fund, Whiteside Clinical Research Institute for their financial support. Publisher Copyright: © 2021 Elsevier Ltd

PY - 2021/8/1

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N2 - Several phosphonium derivatives have been synthesized from Baylis-Hillman (BH) reaction derived allyl bromides and aryl phosphines as mitochondria targeting anticancer agents. In vitro cell proliferation inhibition studies on various solid tumor cell lines indicate that most of the compounds exhibit IC50 values in µM concentrations. Further studies reveal that β-substituted BH bromide derived phosphonium derivatives enhance the biological activity to low µM IC50 values. In vitro metabolic studies show that the lead candidate compound 16 inhibits the production of mitochondrial ATP, increases the proton leak within the mitochondrial membrane and abolishes the spare respiratory capacity in a concentration dependent manner.

AB - Several phosphonium derivatives have been synthesized from Baylis-Hillman (BH) reaction derived allyl bromides and aryl phosphines as mitochondria targeting anticancer agents. In vitro cell proliferation inhibition studies on various solid tumor cell lines indicate that most of the compounds exhibit IC50 values in µM concentrations. Further studies reveal that β-substituted BH bromide derived phosphonium derivatives enhance the biological activity to low µM IC50 values. In vitro metabolic studies show that the lead candidate compound 16 inhibits the production of mitochondrial ATP, increases the proton leak within the mitochondrial membrane and abolishes the spare respiratory capacity in a concentration dependent manner.

KW - Anticancer agent

KW - Baylis-Hillman reaction

KW - MTT and SRB assay

KW - MitoStress test

KW - Phosphonium derivatives

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ER -

Synthesis and biological evaluation of novel 2-alkoxycarbonylallylester phosphonium derivatives as potential anticancer agents

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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