The effect of RO3201195 and a pyrazolyl ketone P38 MAPK inhibitor library on the proliferation of Werner syndrome cells.

Mark C Bagley,Paola G S Murziani,Michal J Rokicki,Matthew C Dix,Mohammed Baashen,Terence Davis,David Kipling,Jessica E Dwyer

doi:10.1039/c5ob02229k

Mark C Bagley, Paola G S Murziani + Show 6 more

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https://doi.org/10.1039/c5ob02229k

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Abstract

Microwave-assisted synthesis of the pyrazolyl ketone p38 MAPK inhibitor RO3201195 in 7 steps and 15% overall yield, and the comparison of its effect upon the proliferation of Werner Syndrome cells with a library of pyrazolyl ketones, strengthens the evidence that p38 MAPK inhibition plays a critical role in modulating premature cellular senescence in this progeroid syndrome and the reversal of accelerated ageing observed in vitro on treatment with SB203580.

Highlights

P38α is one isoform of the mitogen-activated protein kinase (MAPK) intracellular enzymes which are central to the regulation of cytokine biosynthesis and inflammatory cell signalling.[1,2]
As part of our interest in mechanisms of premature cell senescence, we showed that administering the p38α inhibitor SB203580 to Werner syndrome (WS) cells rescues all of the features of accelerated replicative decline.[13]
Α,β-disubstituted alkenes may suffer from steric constraints and so, direct, this approach for the synthesis of benzoylacetonitriles was untested

Summary

Introduction

P38α is one isoform of the mitogen-activated protein kinase (MAPK) intracellular enzymes which are central to the regulation of cytokine biosynthesis and inflammatory cell signalling.[1,2] The reduction of pro-inflammatory cytokine levels offers a means for the treatment of inflammatory disorders such as rheumatoid arthritis and atherosclerosis.[3,4] In addition to inflammatory disorders, p38α is known to play a role in the resistance of various cancers to chemotherapy, cancer proliferation and metastasis.[5,6] This makes p38α a compelling therapeutic target for the design of safe and efficacious inhibitors suitable for clinical investigation.[2,7] Following the discovery that pyridinylimidazole p38α inhibitors such as SB203580 mediate multiple cellular responses,[1] including the production of inflammatory cytokines, a wide variety of structurally-distinct chemotypes[8,9] have been discovered to inhibit this enzyme with notable differences in binding motif.[10] Many of these have been used in stage II or III clinical trials.[11]

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