Function through bio-inspired, synthesis-informed design: step-economical syntheses of designed kinase inhibitors†Dedicated to Max Malacria, a friend and scholar whose science and creative contributions to step-economical synthesis have inspired us all and moved the field closer to the ideal.‡Electronic supplementary information (ESI) available: Synthetic procedures and spectral data. See DOI: 10.1039/c4qo00228hClick here for additional data file.

Paul A Wender,Lauren E Sirois,Alison D Axtman,Jennifer E Golden,Matthew C Stevens,Ryan V Quiroz,Jung-Min Kee

doi:10.1039/c4qo00228h

Paul A Wender, Lauren E Sirois + Show 5 more

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https://doi.org/10.1039/c4qo00228h

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Journal: Organic Chemistry Frontiers	Publication Date: Jan 1, 2014
Citations: 5	License type: cc-by

Affiliation: Stanford University

Abstract

The human kinome comprises over 500 protein kinases. When mutated or over-expressed, many play critical roles in abnormal cellular functions associated with cancer, cardiovascular disease and neurological disorders. Here we report a step-economical approach to designed kinase inhibitors inspired by the potent, but non-selective, natural product staurosporine, and synthetically enabled by a novel, complexity-increasing, serialized [5 + 2]/[4 + 2] cycloaddition strategy. This function-oriented synthesis approach rapidly affords tunable scaffolds, and produced a low nanomolar inhibitor of protein kinase C.

Highlights

Protein kinases catalyse the transfer of a γ-phosphate from ATP to select serine, threonine or tyrosine residues in a range of client proteins, thereby regulating cellular pathways central to proliferation, metabolism, apoptosis, transport, differentiation, and cell–cell signaling.[1,2,3,4] Over-expression and/or mutation of these proteins disrupt homeostatic functions of consequence in cancer, cardiovascular, neuronal, inflammatory, and metabolic diseases.[5,6] Not surprisingly, compounds that control kinase activity by activation or inhibition have emerged as preeminent clinical candidates or drugs for numerous therapeutic indications
We report a step-economical approach to designed kinase inhibitors inspired by the potent, but non-selective, natural product staurosporine, and synthetically enabled by a novel, complexity-increasing, serialized [5 + 2]/[4 + 2] cycloaddition strategy
Our initial indole analogs inhibited protein kinase C (PKC) in the low micromolar range. Further simplification of this series, involving deletion of the indole moiety, gave rise to a second analog series with low nanomolar activity approaching that of the lead natural product, staurosporine

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Function through bio-inspired, synthesis-informed design: step-economical syntheses of designed kinase inhibitors†‡ Cite this: Org. Chem. The human kinome comprises over 500 protein kinases. When mutated or over-expressed, many play critical roles in abnormal cellular functions associated with cancer, cardiovascular disease and neurological disorders. We report a step-economical approach to designed kinase inhibitors inspired by the potent, but non-selective, natural product staurosporine, and synthetically enabled by a novel, complexity-increasing, serialized [5 + 2]/[4 + 2] cycloaddition strategy. This function-oriented synthesis approach rapidly affords tunable scaffolds, and produced a low nanomolar inhibitor of protein kinase C

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