Synthesis and SAR Studies of Neuritogenic Gentiside Derivatives

Abstract

Tetradecyl 2,3-dihydroxybenzoate (ABG-001) has been designed and synthesised as a lead compound to treat Alzheimer's disease, based on structure-activity relationships of gentisides. In this paper, the alkyl chain and ester linkage group of ABG-001 were modified. Consequently, several series of novel gentiside derivatives were designed and synthesised, and their neuritogenic activity was evaluated in PC12 cells. Among all the tested compounds, S-dodecyl 2,3-dihydroxybenzothioate (15d, named as ABG-199) was the most potent; the compound induced significant neurite outgrowth at 0.1 µM, which was comparable to that of nerve growth factor at the optimal concentration of 40 ng/mL and ABG-001 at 1 µM. A brief study on the mechanism of action of ABG-199 revealed that extracellular signal-regulated kinase phosphorylation was involved in ABG-199-induced neurite outgrowth in PC12 cells. Key words neuritogenic activity; thioester; gentiside derivativeAlzheimer's disease (AD) is the most prevalent neurodegenerative disease in aged populations, and the number of cases is rapidly increasing. As one of the most important neurotrophic factors, the nerve growth factor (NGF) is essential for neuronal differentiation, growth, survival, function maintenance and prevention of ageing in central and peripheral systems.

Catechol‐Based Ligands as Potential Metal Chelators Inhibiting Redox Activity in Alzheimer's Disease

“…On the contrary, the chain length is important for activity. In the benzoate series, higher activity was found for derivatives with alkyl chains containing 8–16 carbon atoms (i.e., 13–21 bonds between the two catechol rings) , . So, in order to get ligands able (i) to chelate with high affinity the biologically relevant redox metal ions Cu 2+ and Fe 3+ , and (ii) to promote NGF‐like activity, we designed and synthesized a series of tetradentate bis(2,3‐dihydroxyalkylbenzamide) derivatives having 10–13 bonds between the two catechol rings (Figure ).…”

“…For this reason, this motif is of potential interest for the therapy of neurodegenerative diseases, and series of synthetic 2,3‐dihydroxybenzoates and 2,3‐dihydroxythiobenzoates were synthesized. Their activity as neurite outgrowth inducers, compared to that of NGF, was found to be promising in vitro , …”

The Insulin Receptor: A Potential Target of Amarogentin Isolated from Gentiana rigescens Franch That Induces Neurogenesis in PC12 Cells

“…Interestingly, the mechanism of the action of AMA for its NGF-mimicking effect was different from that of previously reported compounds (such as ABG-001, lindersin B, 3beta,23,28-trihydroxy-12-oleanene 3beta-caffeate and CuB). Tetradecyl 2,3-dihydroxybenzoate (ABG-001) was designed and synthesized as a lead compound in accordance with the gentiside series to induce neurogenesis in PC12 cells by the IGF-1R/PI3K/MAPK signaling pathway [9,10]. Lindersin B from L. crustacea induced neuritogenic activity through the activation of the TrkA/PI3K/ERK signaling pathway [11].…”

“…Given the characteristic of exhibiting sympathetic neuron-like phenotypes under the stimulation of the NGF, the PC12 cell line, which is derived from rat pheochromocytoma cells, is widely used as a model to screen small molecules with NGF-mimicking activities [6]. In previous studies, under the guidance of a PC12 cell bioassay system, several small molecules with NGF-mimicking activities were isolated from traditional Chinese medicines (TCMs) such as Gentiana rigescens Franch, Lindernia crustacean and Desmodium sambuense and the mechanism of the action studies was also identified [7][8][9][10][11][12].…”

Semi‐synthesis and Structure–Activity Relationship of Neuritogenic Oleanene Derivatives

“…[9][10][11] To date, we have isolatedo rsynthesized dozenso fn euritogenic substances. [12][13][14][15][16] To identify new highly effective substances that exhibit low toxicitya nd novel mechanisms,w eh ave steadily pursued the extractiona nd separation of traditional Chinese medicines (TCMs) and synthesized derivatives for structure-activity relationship (SAR) studies. Desmodium sambuense,w hich belongs to the Leguminosae family, is an important TCM.…”