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

Bioorg Med Chem Lett. 2021 Nov 15:52:128411. doi: 10.1016/j.bmcl.2021.128411.

Grady L Nelson ¹, Conor T Ronayne ¹, Lucas N Solano ¹, Sravan K Jonnalagadda ¹, Shirisha Jonnalagadda ¹, Tanner J Schumacher ¹, Zachary S Gardner ¹, Hithardha Palle ², Chinnadurai Mani ², Jon Rumbley ³, Venkatram R Mereddy ⁴

Affiliations

1 Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, USA.
2 Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
3 Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, USA; Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN 55812, USA.
4 Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, USA; Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN 55812, USA; Department of Chemistry and Biochemistry, University of Minnesota Duluth, Duluth, MN 55812, USA. Electronic address: vmereddy@d.umn.edu.

PMID: 34626786 DOI: 10.1016/j.bmcl.2021.128411

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.

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