First Generation of Antioxidant Precursors for Bioisosteric Se-NSAIDs: Design, Synthesis, and In Vitro and In Vivo Anticancer Evaluation

Sandra Ramos-Inza; Cesar Aliaga; Ignacio Encío; Asif Raza; Arun K Sharma; Carlos Aydillo; Nuria Martínez-Sáez; Carmen Sanmartín; Daniel Plano

doi:10.3390/antiox12091666

First Generation of Antioxidant Precursors for Bioisosteric Se-NSAIDs: Design, Synthesis, and In Vitro and In Vivo Anticancer Evaluation

Antioxidants (Basel). 2023 Aug 24;12(9):1666. doi: 10.3390/antiox12091666.

Authors

Sandra Ramos-Inza^{1

2}, Cesar Aliaga³, Ignacio Encío⁴, Asif Raza³, Arun K Sharma³, Carlos Aydillo^{1

2}, Nuria Martínez-Sáez¹, Carmen Sanmartín^{1

2}, Daniel Plano^{1

2}

Affiliations

¹ Department of Pharmaceutical Technology and Chemistry, University of Navarra, Irunlarrea 1, 31008 Pamplona, Spain.
² Instituto de Investigación Sanitaria de Navarra (IdiSNA), Irunlarrea 3, 31008 Pamplona, Spain.
³ Department of Pharmacology, Penn State Cancer Institute, CH72, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
⁴ Department of Health Sciences, Public University of Navarra, Avda. Barañain s/n, 31008 Pamplona, Spain.

Abstract

The introduction of selenium (Se) into organic scaffolds has been demonstrated to be a promising framework in the field of medicinal chemistry. A novel design of nonsteroidal anti-inflammatory drug (NSAID) derivatives based on a bioisosteric replacement via the incorporation of Se as diacyl diselenide is reported. The antioxidant activity was assessed using the DPPH radical scavenging assay. The new Se-NSAID derivatives bearing this unique combination showed antioxidant activity in a time- and dose-dependent manner, and also displayed different antiproliferative profiles in a panel of eight cancer cell lines as determined by the MTT assay. Ibuprofen derivative 5 was not only the most antioxidant agent, but also selectively induced toxicity in all the cancer cell lines tested (IC₅₀ < 10 µM) while sparing nonmalignant cells, and induced apoptosis partially without enhancing the caspase 3/7 activity. Furthermore, NSAID derivative 5 significantly suppressed tumor growth in a subcutaneous colon cancer xenograft mouse model (10 mg/kg, TGI = 72%, and T/C = 38%) without exhibiting any apparent toxicity. To our knowledge, this work constitutes the first report on in vitro and in vivo anticancer activity of an unprecedented Se-NSAID hybrid derivative and its rational use for developing precursors for bioisosteric selenocompounds with appealing therapeutic applications.

Keywords: NSAID; antioxidant; antiproliferative agents; colon cancer; diacyl diselenide; mouse xenograft model; selenium.

Grants and funding

This research was financially supported by the Plan de Investigación de la Universidad de Navarra, PIUNA (2018–19), and the Department of Pharmacology and Penn State Cancer Institute of the Penn State College of Medicine.