Synthesis and Neurotrophic Activity Studies of Illicium Sesquiterpene Natural Product Analogues

Abstract

Neurotrophic natural products hold potential as privileged structures for the development of therapeutic agents against neurodegeneration. However, only a few studies have been conducted to investigate a common pharmacophoric motif and structure-activity relationships (SARs). Here, an investigation of structurally more simple analogues of neurotrophic sesquiterpenes of the illicium family is presented. A concise synthetic route enables preparation of the carbon framework of (±)-Merrilactone A and (±)-Anislactone A/B on a gram scale. This has allowed access to a series of structural analogues by modification of the core structure, including variation of oxidation levels and alteration of functional groups. In total, 15 derivatives of the natural products have been synthesized and tested for their neurite outgrowth activities. Our studies indicate that the promising biological activity can be retained by structurally simpler natural product analogues, which are accessible by a straightforward synthetic route.

Stereodivergent Attached‐Ring Synthesis via Non‐Covalent Interactions: A Short Formal Synthesis of Merrilactone A

“…The chemical space around 4 [19] (although not 4 itself) [18] possesses potent neurotrophic agents which approach the activity of 1 . Since we found 1 and 2 to selectively antagonize GABA A receptors and hyperexcite neurons [8, 20] without convulsion, [20b] access to this chemical space should allow greater exploration of these privileged, neuroactive chemotypes.…”

Three-Membered Rings With Two Oxygen and/or Sulfur Atoms

“…In a study aimed at the preparation of illicium sesquiterpene natural product analogues, the polycyclic epoxide 48 is an important building block, which is available via epoxidation of the cyclopentene fragment of the -oxocarboxylate 47 (Scheme 19). (48) Interestingly, the attempted reaction of 47 with 3d led to a mixture of lactones 49 and 50, whereas the analogous reaction performed, after saponification of the ester group (EtO 2 C), with 3b gave the desired epoxide 48 in a stereoselective manner and in quantitative yield.…”

Total Syntheses of (−)-Majucin and (−)-Jiadifenoxolane A, Complex Majucin-Type Illicium Sesquiterpenes

“…4,5 No doubt such interest has arisen from the long-known GABA-modulatory properties of members of this Illicium class and especially the ability of 2 – 5 (and derivatives) to promote neurotrophic phenotypes in both cultured rat cortical neurons and, more recently, human induced pluripotent stem cells. 3a,3d,5k,6−8 To the best of our knowledge, the neurotrophic activity of 1 has not been reported.…”