Synthesis and biological evaluation of N, N-dialkylcarboxy coumarin-NO donor conjugates as potential anticancer agents

Grady L. Nelson; Conor T Ronayne; Lucas N. Solano; Sravan K. Jonnalagadda; Shirisha Jonnalagadda; Tanner J. Schumacher; Zachary S. Gardner; Hithardha Palle; Chinnadurai Mani; Jon Rumbley; Venkatram R. Mereddy

doi:10.1016/j.bmcl.2021.128411

Synthesis and biological evaluation of N, N-dialkylcarboxy coumarin-NO donor conjugates as potential anticancer agents

Grady L. Nelson, Conor T Ronayne, Lucas N. Solano, Sravan K. Jonnalagadda, Shirisha Jonnalagadda, Tanner J. Schumacher, Zachary S. Gardner, Hithardha Palle, Chinnadurai Mani, Jon Rumbley, Venkatram R. Mereddy

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Abstract

A series of nitric oxide (NO) donor furoxan conjugates of N, N-dialkylcarboxy coumarins have been synthesized as potential anticancer agents. The synthesized compounds have been tested for their in vitro antiproliferative activities on various cancer and noncancerous cell lines. The candidate derivatives exhibit selectivity towards cancer cells with excellent activities in low nM to µM concentrations. In vitro mechanistic studies indicate that the candidate compounds generate substantial NO, inhibit colony formation, and cause apoptosis in cancer cells. A preliminary in vivo tolerance study of the lead candidate 10 in mice indicates that it is well-tolerated, evidenced by zero mortality and normal body weight gains in treated mice. Further translation of the lead derivative 10 using MDA-MB-231 based tumor xenograft model shows good tumor growth reduction.

Original language	English (US)
Article number	128411
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	52
Early online date	Oct 6 2021
DOIs	https://doi.org/10.1016/j.bmcl.2021.128411
State	Published - Nov 15 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

Diphenylsulfonylfuroxan
N N-dialkylcarboxy coumarin
NO donor
Triple-negative breast cancer

UN SDGs

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

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10.1016/j.bmcl.2021.128411

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Nelson, G. L., Ronayne, C. T., Solano, L. N., Jonnalagadda, S. K., Jonnalagadda, S., Schumacher, T. J., Gardner, Z. S., Palle, H., Mani, C., Rumbley, J., & Mereddy, V. R. (2021). Synthesis and biological evaluation of N, N-dialkylcarboxy coumarin-NO donor conjugates as potential anticancer agents. Bioorganic and Medicinal Chemistry Letters, 52, Article 128411. https://doi.org/10.1016/j.bmcl.2021.128411

Nelson, GL, Ronayne, CT, Solano, LN, Jonnalagadda, SK, Jonnalagadda, S, Schumacher, TJ, Gardner, ZS, Palle, H, Mani, C, Rumbley, J & Mereddy, VR 2021, 'Synthesis and biological evaluation of N, N-dialkylcarboxy coumarin-NO donor conjugates as potential anticancer agents', Bioorganic and Medicinal Chemistry Letters, vol. 52, 128411. https://doi.org/10.1016/j.bmcl.2021.128411

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abstract = "A series of nitric oxide (NO) donor furoxan conjugates of N, N-dialkylcarboxy coumarins have been synthesized as potential anticancer agents. The synthesized compounds have been tested for their in vitro antiproliferative activities on various cancer and noncancerous cell lines. The candidate derivatives exhibit selectivity towards cancer cells with excellent activities in low nM to µM concentrations. In vitro mechanistic studies indicate that the candidate compounds generate substantial NO, inhibit colony formation, and cause apoptosis in cancer cells. A preliminary in vivo tolerance study of the lead candidate 10 in mice indicates that it is well-tolerated, evidenced by zero mortality and normal body weight gains in treated mice. Further translation of the lead derivative 10 using MDA-MB-231 based tumor xenograft model shows good tumor growth reduction.",

keywords = "Diphenylsulfonylfuroxan, N N-dialkylcarboxy coumarin, NO donor, Triple-negative breast cancer",

author = "Nelson, {Grady L.} and Ronayne, {Conor T} and Solano, {Lucas N.} and Jonnalagadda, {Sravan K.} and Shirisha Jonnalagadda and Schumacher, {Tanner J.} and Gardner, {Zachary S.} 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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doi = "10.1016/j.bmcl.2021.128411",

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AU - Ronayne, Conor T

AU - Solano, Lucas N.

AU - Jonnalagadda, Sravan K.

AU - Jonnalagadda, Shirisha

AU - Schumacher, Tanner J.

AU - Gardner, Zachary S.

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 - 2021/11/15

Y1 - 2021/11/15

N2 - A series of nitric oxide (NO) donor furoxan conjugates of N, N-dialkylcarboxy coumarins have been synthesized as potential anticancer agents. The synthesized compounds have been tested for their in vitro antiproliferative activities on various cancer and noncancerous cell lines. The candidate derivatives exhibit selectivity towards cancer cells with excellent activities in low nM to µM concentrations. In vitro mechanistic studies indicate that the candidate compounds generate substantial NO, inhibit colony formation, and cause apoptosis in cancer cells. A preliminary in vivo tolerance study of the lead candidate 10 in mice indicates that it is well-tolerated, evidenced by zero mortality and normal body weight gains in treated mice. Further translation of the lead derivative 10 using MDA-MB-231 based tumor xenograft model shows good tumor growth reduction.

AB - A series of nitric oxide (NO) donor furoxan conjugates of N, N-dialkylcarboxy coumarins have been synthesized as potential anticancer agents. The synthesized compounds have been tested for their in vitro antiproliferative activities on various cancer and noncancerous cell lines. The candidate derivatives exhibit selectivity towards cancer cells with excellent activities in low nM to µM concentrations. In vitro mechanistic studies indicate that the candidate compounds generate substantial NO, inhibit colony formation, and cause apoptosis in cancer cells. A preliminary in vivo tolerance study of the lead candidate 10 in mice indicates that it is well-tolerated, evidenced by zero mortality and normal body weight gains in treated mice. Further translation of the lead derivative 10 using MDA-MB-231 based tumor xenograft model shows good tumor growth reduction.

KW - Diphenylsulfonylfuroxan

KW - N N-dialkylcarboxy coumarin

KW - NO donor

KW - Triple-negative breast cancer

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Synthesis and biological evaluation of N, N-dialkylcarboxy coumarin-NO donor conjugates as potential anticancer agents

Abstract

Bibliographical note

Keywords

UN SDGs

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