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. 2015 Jun 3;8(2):257-76.
doi: 10.3390/ph8020257.

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

Mark C Bagley  1 , Mohammed Baashen  2 , Irina Chuckowree  3 , Jessica E Dwyer  4 , David Kipling  5 , Terence Davis  6
Affiliations

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

Mark C Bagley et al. Pharmaceuticals (Basel). .

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.

Keywords: MK2 inhibitor; Suzuki-Miyaura; Werner syndrome; boronic acid; cell aging; cross-coupling; heterocycles; microwave-assisted synthesis; pyrazoles.

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Figures

Figure 1
Figure 1
Inhibitors of p38 MAPK examined in WS cells.
Figure 2
Figure 2
Examples of MK2 inhibitors from different drug discovery programs, showing the use of Suzuki-Miyaura aryl-aryl coupling for late-stage scaffold optimization.
Figure 3
Figure 3
MK2 inhibitor chemotypes and their effect on WS cells.
Figure 4
Figure 4
Increased replicative lifespan (±SD; n = 3) and improvement cellular morphology in WS cells using PF-3644022. Cont = control, SB = SB203580 at 2.5 µM, PF1.0 and PF2.0 = PF-3644022 at 1.0 and 2.0 µM respectively. White bar = 100 µm (for methods see experimental section).
Figure 5
Figure 5
Disconnective approach to the synthesis of PF-3644022, utilizing an early-stage Suzuki-Miyaura cross-coupling reaction.
Figure 6
Figure 6
Synthesis of chloroquinoline 11 and subsequent Suzuki-Miyaura cross-coupling.
Figure 7
Figure 7
Scaffold-hopping strategy of Velcicky et al. [53], showing the use of Suzuki-Miyaura aryl-aryl coupling for scaffold optimization.
Figure 8
Figure 8
Suzuki-Miyaura cross-coupling for the synthesis of 6-indolyl scaffolds.
Figure 9
Figure 9
Microwave-assisted synthesis of the MK2 inhibitor 26 using a Suzuki-Miyaura cross-coupling.
See this image and copyright information in PMC

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