Chemodivergent manganese-catalyzed C–H activation: modular synthesis of fluorogenic probes

Abstract

Bioorthogonal late-stage diversification of amino acids and peptides bears enormous potential for drug discovery and molecular imaging. Despite major accomplishments, these strategies largely rely on traditional, lengthy prefunctionalization methods, heavily involving precious transition-metal catalysis. Herein, we report on a resource-economical manganese(I)-catalyzed C–H fluorescent labeling of structurally complex peptides ensured by direct alkynylation and alkenylation manifolds. This modular strategy sets the stage for unraveling structure-activity relationships between structurally discrete fluorophores towards the rational design of BODIPY fluorogenic probes for real-time analysis of immune cell function.

Activatable Fluorophores for Imaging Immune Cell Function

“… 2021 12 . 3 Rational design of BODIPY-based fluorogenic probes to monitor changes in the membrane fluidity of T cells and their application in fluorescence-based screens to identify small molecule modulators of T cell activity.…”

“…As an example, our group recently reported the rational design of BODIPY-based fluorogenic probes to monitor changes in the membrane fluidity of T cells as direct reporters of their activity. 3 These activatable probes were based on molecular rotors that emitted strong fluorescence in response to the cholesterol found in the membranes of T cells ( Figure 5 b). The probes contained a fatty acid chain to facilitate anchoring to the plasma membrane and were used in a fluorescence-based screen to identify small molecule modulators of Jurkat T cells and validate the findings in primary human CD8+ T cells.…”

PIII‐Directed Late‐Stage Ligation and Macrocyclization of Peptides with Olefins by Rhodium Catalysis

“…[2] Chemical modifications of peptides often improve their biological activities and pharmacokinetics. [3] Metal-catalyzed CÀ H functionalization has emerged as a promising strategy for late-stage peptide modification, [4] with contributions by groups of Albericio, [5] Lavilla, [5b] Ackermann, [6] Yu, [7] Chen, [8] Shi [9] and our group, [10] amongst others. [11] Directing groups are usually required in these methods, in which N-and O-containing directing groups display compatibility with peptides and allow their bioconjugation with functional molecules.…”

“…Metal‐catalyzed C−H functionalization has emerged as a promising strategy for late‐stage peptide modification, [4] with contributions by groups of Albericio, [5] Lavilla, [5b] Ackermann, [6] Yu, [7] Chen, [8] Shi [9] and our group, [10] amongst others [11] . Directing groups are usually required in these methods, in which N‐ and O‐containing directing groups display compatibility with peptides and allow their bioconjugation with functional molecules [6a,c, 12] . Tryptophan (Trp) residues are of particular interest in the modification of peptides due to their unique chemical reactivity and biological functions [13] .…”

Late-Stage Functionalization and Diversification of Peptides by Internal Thiazole-Enabled Palladium-Catalyzed C(sp3)–H Arylation

“…Site-selective fluorescent labeling of bioactive peptides is an important strategy to investigate their modes of action. Bioconjugation of fluorophore BODIPY to peptides has been achieved via C–H functionalization. − Using BODIPY 2w , we successfully achieved site-selective fluorophore bioconjugation via Pd-catalyzed arylation on Val and Ala in tripeptides 1a and 1r , respectively, generating mono- and di-BODIPY-labeled peptides (Figure A). The bioactivity of BODIPY-labeled peptides was evaluated by cell staining assays.…”