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

Maodie Wang,Guanyu Zhang,M Graça H Vicente,Kevin M Smith,Petia Bobadova-Parvanova

doi:10.1021/acs.joc.1c02328

Maodie Wang, Guanyu Zhang + Show 3 more

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https://doi.org/10.1021/acs.joc.1c02328

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Abstract

A series of α-amino acid–BODIPY derivatives were synthesized using commercially available N-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 BF2–BODIPY. Cellular uptake and cytotoxicity studies using the human HEp2 cell line show that both the presence of an N,O-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 (IC50 ∼ 22 μM), while the spiro-His-BODIPY was the most efficiently internalized, localizing preferentially in the cell lysosomes, ER, and mitochondria.

Highlights

Boron dipyrrin or boron dipyrromethene (BODIPY) dyes[1−6] are a class of boron-coordinated organic dyes that display a multitude of highly desirable properties for various applications, including good solubility in various solvents, large molar extinction coefficients, high fluorescence quantum yields, relatively sharp absorption and emission bands, low cytotoxicity, and structural tunability
As suggested by our previous findings,[32] this result is probably due to the increased rigidity around the boron center in these conformationally restricted BODIPYs, which minimizes vibrations in-and-out of the dipyrrin plane
Pubs.acs.org/joc polar (Tyr, Ser), and nonpolar (Met) side chains, were synthesized in moderate yields from an in situ prepared BCl2− BODIPY and N(Boc)-L-amino acids, at room temperature. The stability of these conformationally restricted BODIPYs depends on the amino acid binding mode and the basicity of its side chain, with the acidic, polar, and moderate basic (i.e., His) mono-linear amino acid−BODIPY derivatives being the most stable

Summary

Introduction

Boron dipyrrin or boron dipyrromethene (BODIPY) dyes[1−6] are a class of boron-coordinated organic dyes that display a multitude of highly desirable properties for various applications, including good solubility in various solvents, large molar extinction coefficients, high fluorescence quantum yields, relatively sharp absorption and emission bands, low cytotoxicity, and structural tunability. With these extraordinary properties, BODIPY dyes have been widely applied in, for example, live-cell bioimaging,[7,8] photodynamic therapy,[9,10] fluorescent sensing,[11] dye-sensitized solar cells,[12] and viscosity detection.[13]. Only a few reports have explored bidentate B-spiroBODIPYs.[26−28]

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