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

• Main Authors: Sandra Ramos-Inza (Author), Cesar Aliaga (Author), Ignacio Encío (Author), Asif Raza (Author), Arun K. Sharma (Author), Carlos Aydillo (Author), Nuria Martínez-Sáez (Author), Carmen Sanmartín (Author), Daniel Plano (Author)
• Format: Book
• Published: MDPI AG, 2023-08-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.3390/antiox12091666; 2076-3921
• Keywords: selenium; diacyl diselenide; NSAID; antiproliferative agents; antioxidant; colon cancer; Therapeutics. Pharmacology; RM1-950
• Source: Antioxidants, Vol 12, Iss 9, p 1666 (2023)

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 <b>5</b> 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 <b>5</b> 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.