Synthesis and biological evaluation of arylphosphonium-benzoxaborole conjugates as novel anticancer agents

• Published in: Bioorganic & medicinal chemistry letters 2020-07, Vol.30 (14), p.127259-127259, Article 127259
• Main Authors: Jonnalagadda, Sravan K., Wielenberg, Kevin, Ronayne, Conor T., Jonnalagadda, Shirisha, Kiprof, Paul, Jonnalagadda, Subash C., Mereddy, Venkatram R.
• Format: Article
• Language: English
• Subjects: Benzoxaborole; Cell viability; Glycolysis stress test; Mitochondrial fragmentation; Mitochondrial stress test; Phosphonium salts
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2020.127259

[Display omitted] Arylphosphonium-benzoxaborole conjugates have been synthesized as potential mitochondria targeting anticancer agents. The synthesized compounds have been tested for their effects on cell viability in various solid tumor cell lines including breast cancer 4T1 and MCF-7, pancreatic cancer MIAPaCa-2 and colorectal adenocarcinoma WiDr. Compound 6c is designated as a lead compound for further studies due to its enhanced effects on cell viability in the above-mentioned cell lines. Seahorse Xfe96 based metabolic assays reveal that the lead candidate 6c inhibits mitochondrial respiration in 4T1 and WiDr cell lines as evidenced by the reduction of mitochondrial ATP production and increase in proton leak. Epiflourescent microscopy experiments also illustrate that 6c causes significant mitochondrial fragmentation in 4T1 and WiDr cells, morphologically consistent with programmed cell death. Our current studies illustrate that arylphosphonium-benzoxaborole conjugates have potential to be further developed as anticancer agents.