Cascade reactions leading to the mechanism of action of vinaxanthone and xanthofulvin, natural products that drive nerve repair

TETRAHEDRON

卷:74

Article; Proceedings Paper

Eliasen, Anders M.¹  Chin, Matthew R.²  Axelrod, Abram J.³  Abagyan, Ruben⁴  Siegel, Dionicio⁴ 

[1] Calif Inst Biomed Res, La Jolla, CA 92037 USA

[2] Gilead Sci Inc, Foster City, CA 94404 USA

[3] Sloan Kettering Inst Canc Ctr Res, Lab Bioorgan Chem, New York, NY 10021 USA

[4] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, La Jolla, CA 92093 USA

关键词: Methodology;    Total synthesis;    Biosynthesis;    Natural product;    Regeneration;    SUCNR1;    Succinate receptor;    Allosteric;    GPCR;   

DOI  :  10.1016/j.tet.2018.02.068

来源: Elsevier

【 摘 要 】

The natural products vinaxanthone and xanthofulvin promote regeneration in animal models of spinal cord injury and corneal transplant. However, inhibition of the initially described biological target of these compounds, semaphorin 3A, does not fully account for the recovery demonstrated in vivo following administration of the natural products. Through chemical synthesis substantial quantities of both natural products have been accessed with early reaction development paving the way for synthesizing both compounds. The success of a model system, first disclosed herein, translated to the syntheses of both natural products. Following from this we also report for the first time the discovery of a new target of the natural products, the succinate receptor 1 (SUCNR1). Both natural products function as positive allosteric modulators of SUCNR1. As the first known allosteric modulators of SUCNR1, the compounds represent powerful new tools to understand the pharmacology of SUCNR1 and its control of growth and cellular defense. (C) 2018 Elsevier Ltd. All rights reserved.

【 授权许可】

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