Microwave-Assisted Synthesis of a MK2 Inhibitor by Suzuki-Miyaura Coupling for Study in Werner Syndrome Cells.

Mark Bagley,Jessica Dwyer,Irina Chuckowree,Mohammed Baashen,David Kipling,Terence Davis

doi:10.3390/ph8020257

Mark Bagley, Jessica Dwyer + Show 4 more

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https://doi.org/10.3390/ph8020257

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Abstract

Microwave-assisted Suzuki-Miyaura cross-coupling reactions have been employed towards the synthesis of three different MAPKAPK2 (MK2) inhibitors to study accelerated aging in Werner syndrome (WS) cells, including the cross-coupling of a 2-chloroquinoline with a 3-pyridinylboronic acid, the coupling of an aryl bromide with an indolylboronic acid and the reaction of a 3-amino-4-bromopyrazole with 4-carbamoylphenylboronic acid. In all of these processes, the Suzuki-Miyaura reaction was fast and relatively efficient using a palladium catalyst under microwave irradiation. The process was incorporated into a rapid 3-step microwave-assisted method for the synthesis of a MK2 inhibitor involving 3-aminopyrazole formation, pyrazole C-4 bromination using N-bromosuccinimide (NBS), and Suzuki-Miyaura cross-coupling of the pyrazolyl bromide with 4-carbamoylphenylboronic acid to give the target 4-arylpyrazole in 35% overall yield, suitable for study in WS cells.

Highlights

Werner syndrome (WS) is an example of a monogenic segmental progeroid syndrome—a rare human autosomal recessive genetic instability syndrome that mimics many, but not all, of the polygenic features of physiological aging [1,2]
Given that our goal was the introduction of a 6-methyl-3-pyridyl substituent at C-7, we set out to incorporate the Suzuki-Miyaura coupling of the pyridinylboronic acid 10a and 2-chloroquinoline
Suzuki-Miyaura cross-coupling reactions have been investigated for the synthesis of three different

Summary

Introduction

Werner syndrome (WS) is an example of a monogenic segmental progeroid syndrome—a rare human autosomal recessive genetic instability syndrome that mimics many, but not all, of the polygenic features of physiological aging [1,2]. It was first characterized by Dr Otto Werner [3] and its modern diagnosis often relies upon knowledge of previous family incidence and/or presentation with a series of clinical symptoms, including juvenile bilateral cataracts, scleroderma-like skin and premature graying of the hair [4].

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