Chemoselective seleno-click amidation in kinetic target-guided synthesis

Abstract

Capitalizing on our previous kinetic target-guided synthesis (KTGS) involving the sulfo-click reaction to form N-acylsulfonamide-linked inhibitors in the presence of the protein-protein interaction target Mcl-1, we herein report a seleno-click approach for amide-linked inhibitors of Mcl-1. The seleno-click reaction leverages the enhanced reactivity of selenocarboxylates, enabling the templated amidation with electron-rich azides, thereby expanding the scope of KTGS. The potential of this approach is demonstrated by generating N-benzyl-5-(4-isopropylthiophenol)-2-hydroxyl nicotinamide, a known Mcl-1 inhibitor featuring an amide, via KTGS at 37 °C against Mcl-1. Notably, the seleno-click strategy was also effective at 4 °C, offering a variant for thermally sensitive biological targets.

Figure 1:

Identification and quantification of nicotinamide derivative 1 by LC-MS/MS-dMRM analysis of KTGS incubations of selenocarboxylate fragment 3 with benzyl azide fragment 4 with and without Mcl-1. (a) LC-MS/MS trace of incubations at 37 °C. (b) LC-MS/MS trace of incubations at 4 °C. (c) LC-MS/MS trace of the synthetic nicotinamide derivative 1 of a known concentration (20 nM) as a standard reference compound.

Scheme 1:

An overview of past and current KTGS amidations.

Scheme 2:

Binary fragment KTGS approach using the seleno-click amidation reaction.