Syntheses and Investigations of Conformationally Restricted, Linker-Free α-Amino Acid-BODIPYs via Boron Functionalization

• Published in: Journal of organic chemistry 2021-12, Vol.86 (24), p.18030-18041
• Main Authors: Wang, Maodie, Zhang, Guanyu, Bobadova-Parvanova, Petia, Smith, Kevin M, Vicente, M Graça H
• Format: Article
• Language: English
• Subjects: Amino Acids; Boron; Boron Compounds - pharmacology; Crystallography, X-Ray; Humans
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/acs.joc.1c02328

A series of α-amino acid-BODIPY derivatives were synthesized using commercially available -Boc-l-amino acids, via boron functionalization under mild conditions. The mono-linear, mono-spiro, and di-amino acid-BODIPY derivatives were obtained using an excess of basic (histidine, lysine, and arginine), acidic (aspartic acid), polar (tyrosine, serine), and nonpolar (methionine) amino acid residues, in yields that ranged from 37 to 66%. The conformationally restricted mono-spiro- and di-amino acid-BODIPYs display strong absorptions in the visible spectral region with high molar extinction coefficients and significantly enhanced fluorescence quantum yields compared with the parent BF -BODIPY. Cellular uptake and cytotoxicity studies using the human HEp2 cell line show that both the presence of an , -bidentate spiro-ring and basic amino acids (His and Arg) increase cytotoxicity and enhance cellular uptake. Among the series of BODIPYs tested, the spiro-Arg- and spiro-His-BODIPYs were found to be the most cytotoxic (IC ∼ 22 μM), while the spiro-His-BODIPY was the most efficiently internalized, localizing preferentially in the cell lysosomes, ER, and mitochondria.