1. Expedient Synthesis and Characterization of π-Extended Luciferins.
- Author
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Caldwell DR, Townsend KM, Kolbaba-Kartchner B, Hadjian T, Ivanic J, Love AC, Malvar B, Mills J, Prescher JA, and Schnermann MJ
- Subjects
- Molecular Structure, Naphthalenes chemistry, Naphthalenes chemical synthesis, Luminescent Agents chemistry, Luminescent Agents chemical synthesis, Luminescent Measurements, Luciferases metabolism, Luciferases chemistry, Firefly Luciferin chemistry, Coumarins chemistry, Coumarins chemical synthesis
- Abstract
Bioluminescence imaging enables the sensitive tracking of cell populations and the visualization of biological processes in living systems. Bioluminescent luciferase/luciferin pairs with far-red and near-infrared emission benefit from the reduced competitive absorption by blood and tissue while also facilitating multiplexing strategies. Luciferins with extended π-systems, such as AkaLumine and recently reported CouLuc-1 and -3, can be used for bioluminescence imaging in this long wavelength regime. Existing synthetic routes to AkaLumine and similar π-extended compounds require a multistep sequence to install the thiazoline heterocycle. Here we detail the development of a two-step strategy for accessing these molecules via a Horner-Wadsworth-Emmons reaction and cysteine condensation sequence from readily available aldehyde starting materials. We detail an improved synthesis of AkaLumine, as well as the corresponding two-carbon homologues, Tri- and Tetra-AkaLumine. We then extended this approach to prepare coumarin- and naphthalene-derived luciferins. These putative luciferins were tested against a panel of luciferases to identify capable emitters. Of these, an easily prepared naphthalene derivative exhibits photon emission on par with that of the broadly used Akaluc/AkaLumine pair with similar emission maxima. Overall, this chemistry provides efficient access to several bioluminescent probes for a variety of imaging applications.
- Published
- 2024
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