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

Abstract

Neurotrophic factors, now termed neurotrophins, which belong to a class of polypeptidyl agents, have been shown to potentially be beneficial for the treatment of neurodegenerative diseases such as Alzheimer's disease, because endogenous neurotrophic factors (NGF, BDNF, NT3, NT4) have been recognized to play critical roles in the promotion of neurogenesis, differentiation, and neuroprotection throughout the development of the central nervous system. However, high-molecular weight proteins are unable to cross the blood-brain barrier and are easily decomposed by peptidase under physiological conditions. To address this issue, small molecules that can mimic the functions of neurotrophic factors would be promising alternatives for the treatment of neurodegenerative disease. We have continued to search for natural products having typical neurotrophic properties, which can cause neurogenesis, enhance neurite outgrowth, and protect neuronal death using three cellular systems (PC12, rat cortical neurons, and MEB5 cells). In this review, we summarize the neurotrophic activities and synthesis of dimeric isocuparane-type sesquiterpenes from the liverwort, Mastigophora diclados, the mechanism of neurotrophic neolignans, magnolol, honokiol and their sesquiterpene derivatives, and introduce unique neurotrophin-mimic natural products, including seco-prezizaane-type sesquiterpenes from the Illicium species, vibsane-type diterpenes from Viburnum awabuki, and miscellaneous natural products with neurotrophic effects discovered by us.

Neurite Outgrowth-Promoting Compounds from the Petals of Paeonia lactiflora in PC12 Cells

“…Isorhamnetin-3-Oglucoside (1) and astragalin (2), which promote neurite outgrowth, also increased the neurofilament expression. The compounds promoting neurite outgrowth are thought to be effective for treating cognitive dysfunctions, such as Alzheimer's disease, by helping the differentiation of neurons associated with memory and learning in the brain [30]. Isorhamnetin-3-O-glucoside (1) and astragalin (2) have strong neurite outgrowth-promoting activities; however, they are metabolized by human intestinal flora to create aglycons [31].…”

Neuroprotective Potency of Neolignans in Magnolia officinalis Cortex Against Brain Disorders

“…Moreover, MN (1) and HK (2) are isomers, whose only difference is the relative position of one hydroxyl group and allyl group. The 4′-hydroxy group and the 5-allyl group are the key to higher neurotrophic activity of HK (2) than that of MN (1) ( Fukuyama et al, 2020 ). Furthermore, both HK (2) and MN (1) exerted neuroprotective effects, which might be related to penetrate the blood-brain barrier (BBB) ( Kantham et al, 2017 ).…”

Synthetic Studies Concerned with the Proposed Structure of Ribisin F, a Compound with Nerve Growth Factor Potentiating Activity Isolated from the Medicinal Fungus Phellinus ribis

“…[1,2] As such they have been touted as possible leads for the development of drugs to treat neurodegenerative diseases. [3] These features have prompted studies on their synthesis [4][5][6] and our efforts [4] in this regard led to the preparation of congeners 1-4 and so resulting in the confirmation of the structures assigned to ribisins A and D and corrections to those originally assigned to congeners B and C. Furthermore, prior to the report of the isolation of ribisin G by Dong et al [2] we had prepared this compound [4b] and have recently shown [7] that there is good agreement between the spectral data sets recorded on the naturally-and synthetically-derived materials. Since our synthetic studies on the ribisins had resulted in the generation of a suite of analogues [4] we evaluated these, as well as natural products 1-4 and 7, for their neuroprotective properties and thereby established [7] that certain analogues and derivatives of the ribisins are quite active in this regard and most likely exert their beneficial effects by activation of the Keap1-Nrf2-ARE pathway.…”

“…The structurally distinct benzofuran‐containing natural products 1 – 7 (Figure 1), named ribisins A–G respectively, have been isolated from the medicinal fungus Phellinus ribis and reported to exert nerve growth factor (NGF)‐potentiating activities [1,2] . As such they have been touted as possible leads for the development of drugs to treat neurodegenerative diseases [3] . These features have prompted studies on their synthesis [4–6] and our efforts [4] in this regard led to the preparation of congeners 1 – 4 and so resulting in the confirmation of the structures assigned to ribisins A and D and corrections to those originally assigned to congeners B and C. Furthermore, prior to the report of the isolation of ribisin G by Dong et al [2] .…”