Chemistry and Neurotrophic Activities of (–)-Talaumidin and Its Derivatives

Abstract

Talaumidin (1), a 2,5-biaryl-3,4-dimethyltetrahydrofuran lignan isolated from Aristolochia arcuata Masters, exhibits significant neurite-outgrowth promotion and neuroprotection in primary cultured rat cortical neurons and in NGF-differentiated PC12 cells. The first enantioselective total synthesis of 1 was achieved by a flexible and reliable synthetic pathway involving an Evans asymmetric aldol reaction, as well as a stereocontrolled hydroboration and Friedel-Crafts arylation, to construct the four contiguous chiral centers on the tetrahydrofuran (THF) ring of 1. In order to investigate the stereochemistry-activity relationship of 1, a systematic synthesis of all diastereomers of 1 was accomplished by applying the synthetic strategy used for natural product 1. The evaluation of neurite-outgrowth promotion by all of the synthesized diastereomers indicated that the (-)-(1S,2R,3S,4R)-isomer 1e was significantly more active than naturally occurring 1. Additionally, we established a synthetic methodology for talaumidin derivatives that could be used to prepare a variety of analogs in a few steps and on a large scale. The synthesized racemic analog rac-1e (56a) exhibited neurite-outgrowth promoting activity in NGF-differentiated PC12 cells to the same degree as the optically active (-)-1e, revealing that a relative configuration bearing all-cis-substituents is important for potent neurotrophic activity, whilst the absolute configuration does not affect activity. Fourteen analogs based on (±)-56a were prepared via the same synthetic methodology. Among them, 56b with a methylenedioxy group on both benzene rings was found to exhibit the most significant neurite outgrowth promotion. In addition, 56a and 56b induced regeneration of the mouse optic nerve in vivo, and their activity was higher than that of talaumidin, as well as their in vitro measured activity. Furthermore, the structure-activity relationship of 56b indicated that the two benzene rings were essential structures, and that the methyl groups on the THF ring could enhance the neurotrophic activity. This result suggests that the two benzene rings of the talaumidin derivatives are essential structures for neurotrophic activity, while the two methyl groups on the THF ring can enhance neurite-outgrowth activity. Finally, it was observed that 1 and derivatives 56a and 56b exhibited potent regenerative activity in the injured mouse optic nerve in vivo.

The search for, and chemistry and mechanism of, neurotrophic natural products

“…The data are expressed ± S.E. (n = 80); student's t test vs. control, ## p < 0.01; Dunnett's t test vs. control, **p < 0.01 [138] Finally, it should be noted that a comprehensive review on (-)-talaumidin, a neurotrophic 2,5-biaryl-3,4-dimethylhydrofuran lignan, has been published quite recently [149]. Given the increasing interest in neurotrophin-mimic compounds, we suggest that readers refer to a recent review covering another topic of neurotrophic natural products.…”

Exploring F/CF3substituted oxocarbenium ions for the diastereoselective assembly of highly substituted tetrahydrofurans

“…Tetrahydrofurans (THFs), as well as their analogues in higher oxidation states, are important structural motifs found in both natural and unnatural bioactive products. 1 Examples include highly substituted natural products (+)-fragransin A2, 2 jiadifenin, 3 (−)-talaumidin, 4 sofosbuvir, 5 a polymerase NSSB inhibitor employed in curative treatments of hepatitis C virus or bicyclic pyridinone 1 6 used in neurological disorders treatment. All exhibit an aryl group in position 2 and/or a methyl group in position 3 (Fig.…”