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Engineering Central Substitutions in Heptamethine Dyes for Improved Fluorophore Performance.

Lei GuoMeek YangBin DongSeth LewmanAlex Van HornShang Jia
Published in: JACS Au (2024)
As a major family of red-shifted fluorophores that operate beyond visible light, polymethine dyes are pivotal in light-based biological techniques. However, methods for tuning this kind of fluorophores by structural modification remain restricted to bottom-up synthesis and modification using coupling or nucleophilic substitutions. In this study, we introduce a two-step, late-stage functionalization process for heptamethine dyes. This process enables the substitution of the central chlorine atom in the commonly used 4'-chloro heptamethine scaffold with various aryl groups using aryllithium reagents. This method borrows the building block and designs from the xanthene dye community and offers a mild and convenient way for the diversification of heptamethine fluorophores. Notably, this efficient conversion allows for the synthesis of heptamethine-X, the heptamethine scaffold with two ortho-substituents on the 4'-aryl modification, which brings enhanced stability and reduced aggregation to the fluorophore. We showcase the utility of this method by a facile synthesis of a fluorogenic, membrane-localizing fluorophore that outperforms its commercial counterparts with a significantly higher brightness and contrast. Overall, this method establishes the synthetic similarities between polymethine and xanthene fluorophores and provides a versatile and feasible toolbox for future optimizing heptamethine fluorophores for their biological applications.
Keyphrases
  • visible light
  • fluorescent probe
  • healthcare
  • magnetic resonance
  • magnetic resonance imaging
  • molecular dynamics
  • ionic liquid
  • current status
  • highly efficient