Photoredox‐Mediated Hydrogen Isotope Exchange Reactions of Amino‐Acids, Peptides, and Peptide‐Derived Drugs

Abstract

Hydrogen isotopically labelledc ompoundsa re essential diagnostic tools in drug research and development, as they provide vital informationa bout the biological metabolism of drug candidates and their metabolites. Herein we report ap hotoredox-initiated hydrogen atom transfer(HAT) protocol which efficiently and selectively introduces deuterium or tritium at C(sp 3)ÀHb onds, utilizing heavy water (D 2 Oo rT 2 O) as the hydrogen isotope source, and ag uanidine base.T his protocol has been successfully appliedto the incorporationo fd euteriumi ns everal amino acids (lysine, glycine and proline) and small peptides. Finally,t he method has been applied to tritium,b ecause tritium-labelled peptides are essential for application in biological experiments,s uch as ligand-binding assays,o ra bsorption, distribution, metabolism, and excretion (ADME) studies.

Organic thermally activated delayed fluorescence (TADF) compounds used in photocatalysis

“…129d). 300 In the former reaction, amino radicals are used a XAT reagents in order to functionalise aryl and alkyl halides, as previously mentioned. 186 In the proposed mechanism, the excited PC is used to oxidise TEA, forming the a-aminoalkyl radical.…”

Catalytic Hydrogen Isotope Exchange Reactions in Late-Stage Functionalization

“…Eighteen drug molecules, including both cyclic and acyclic amines, have been labeled with either deuterium or tritium at the -position to nitrogen in high incorporation. More recently, Derdau's group applied this protocol to the incorporation of deuterium and tritium in peptides 19 (Scheme 5b).…”

“…More recently, Derdau's group applied this protocol to the incorporation of deuterium and tritium in peptides (Scheme 5b). 19 In 2020, Wang reported a formyl-selective deuteration of aldehydes via a synergistic combination of light-driven, polyoxometalate-facilitated HAT and thiol catalysis. 20 Pregnenolone and ibuprofen derivatives were deuterated with high levels of incorporation (Scheme 6a).…”

Visible-Light Photocatalysis as an Enabling Technology for Drug Discovery: A Paradigm Shift for Chemical Reactivity

“…This deuteration or tritiation protocol was also applicable to various commercially available drugs containing a variety of alkyl amine scaffolds, such as the macrolide drug clarithromycin ([ 2 H]- 37 , [ 3 H]- 38 ) showcasing the functional group tolerance of this method. Recently, Sanofi-Aventis reported a related protocol to accomplish the deuteration and tritiation of linear peptides under photoredox conditions …”