Cytotoxicity of Amino‐BODIPY Modulated via Conjugation with 2‐Phenyl‐3‐Hydroxy‐4(1H)‐Quinolinones

• Published in: ChemistryOpen (Weinheim) Vol. 10; no. 11; pp. 1104 - 1110
• Main Authors: Porubský, Martin, Vychodilová, Kristýna, Milićević, David, Buděšinský, Miloš, Stanková, Jarmila, Džubák, Petr, Hajdúch, Marián, Hlaváč, Jan
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.11.2021; John Wiley and Sons Inc; Wiley-VCH
• Subjects: amino-BODIPY dyes; Cancer; Cleavage; Conjugation; cytotoxic activity; Cytotoxicity; disulfide linkers; Disulfides; Dyes; Fibroblasts; Fluorescence; Fluorescent Dyes; Glutathione; hydroxyquinolinones; Leukemia; Microscopy; Quinolones - toxicity; Toxicity; disulfide linkers; cytotoxic activity; amino-BODIPY dyes; hydroxyquinolinones; glutathione
• ISSN: 2191-1363; 2191-1363
• DOI: 10.1002/open.202100025

The combination of cytotoxic amino‐BODIPY dye and 2‐phenyl‐3‐hydroxy‐4(1H)‐quinolinone (3‐HQ) derivatives into one molecule gave rise to selective activity against lymphoblastic or myeloid leukemia and the simultaneous disappearance of the cytotoxicity against normal cells. Both species′ conjugation can be realized via a disulfide linker cleavable in the presence of glutathione characteristic for cancer cells. The cleavage liberating the free amino‐BODIPY dye and 3‐HQ derivative can be monitored by ratiometric fluorescence or by the OFF‐ON effect of the amino‐BODIPY dye. A similar cytotoxic activity is observed when the amino‐BODIPY dye and 3‐HQ derivative are connected through a non‐cleavable maleimide linker. The work reports the synthesis of several conjugates, the study of their cleavage inside cells, and cytotoxic screening. Amino‐BODIPY conjugates with various 2‐phenyl‐3‐hydroxyquinolinones (3‐HQs) connected via cleavable disulfide linker and non‐cleavable maleimide linker were prepared and tested on cytotoxic activity and fluorescent ratiometric “OFF‐ON” monitoring of cleavage inside the cells was demonstrated. Disulfide conjugates exhibited improved cytotoxicity compared to the free 3‐HQs whereas non‐cleavable maleimide conjugates stayed inactive proving that disulfide linker is responsible for cleavage inside the cells and therefore resulting in cytotoxicity of disulfide Amino‐BODIPY‐3HQ conjugates.