Gentisides C–K: Nine new neuritogenic compounds from the traditional Chinese medicine Gentiana rigescens Franch

Abstract

Nine new alkyl 2,3-dihydroxybenzoates, gentisides C-K, were isolated from the traditional Chinese medicine Gentiana rigescens Franch. Their structures and stereochemistry were elucidated by spectroscopic methods, and comparison of the specific rotation with that of the gentiside B. These metabolites are additional members of the gentisides which belong to a novel class of neuritogenic compounds. They are structurally different from one another because they possess varying alkyl chain lengths, with or without an isobutyl or isopropyl group at the end of the alkyl chain. These compounds are potent inducers of neurite outgrowth on PC12 cells. The gentiside C possessing the shortest alkyl chain length exhibited the highest neuritogenic activity among all of the gentisides. Gentiside C showed a significant neuritogenic activity at 1 μM against PC12 cells comparable to that seen for the best nerve growth factor (NGF) concentration of 40 ng/mL. In addition, evident neuritogenic activity was observed in the cells when treated with gentiside C at a concentration as low as 0.03 μM. The structure-activity relationships within the gentisides A-K revealed that alkyl chain length is important for the activity, but structure diversity at the end of the alkyl chain is not.

Synthesis and SAR Studies of Neuritogenic Gentiside Derivatives

“…[5][6][7] Gentisides are a novel class of neuritogenic phenolic lipids, which we previously isolated from the traditional Chinese medicine Gentiana rigescens FRANCH 8,9) (Fig. 1).…”

Neuritogenic Surfaces using Natural Product Analogs

“…[ 28 ] This compound offers several benefi ts such as ease of access and excellent neurite outgrowth inducing capabilities in the PC12 cell assay. [ 29,30 ] In addition, as amphiphiles [ 31 ] and polyphenols [32][33][34][35][36][37][38] are known to adsorb to surfaces, we therefore hypothesized that compound 1 might allow for the assembly of neuritogenic surfaces via an operationally simple dip-coating approach.Preliminary experiments were carried out in order to test this hypothesis. In a fi rst setting, a 1 × 10 −3 M solution of compound 1 in THF was mixed in a 1:10 ratio with a 0.01% aqueous solution of collagen.…”

“…Among three hit compounds (vide infra), we chose the natural product analog 1 , ( Figure 1 ), a truncated form of gentiside B 2 , recently reported by Qi and co-workers as our initial lead structure. [28][29][30] Compound 1 is a simplifi ed analog of the natural product gentiside B, isolated from Gentiana rigescens, a plant used in traditional Chinese medicine. [ 28 ] This compound offers several benefi ts such as ease of access and excellent neurite outgrowth inducing capabilities in the PC12 cell assay.…”

Termitomycesphins G and H, Additional Cerebrosides from the Edible Chinese MushroomTermitomyces albuminosus

“…7) Our previous search for these compounds with the PC12 cell line enabled us to isolate six novel cerebrosides, 8,9) a series of steroidal glycosides 10) and alkyl benzoates. 11,12) Termitomycesphins A-F, 8,9) which were isolated from the Chinese mushroom, Termitomyces albuminosus (Berk.) Heim., showed significant neuritogenic activity.…”