Design and Synthesis of Dimeric Securinine Analogues with Neuritogenic Activities

Abstract

Neurite outgrowth is crucial during neuronal development and regeneration, and strategies that aim at promoting neuritogenesis are beneficial for reconstructing synaptic connections after neuronal degeneration and injury. Using a bivalent analogue strategy as a successful approach, the current study identifies a series of novel dimeric securinine analogues as potent neurite outgrowth enhancers. Compounds 13, 14, 17-19, and 21-23, with different lengths of carbon chain of N,N-dialkyl substituting diacid amide linker between two securinine molecules at C-15 position, exhibited notable positive effects on both neuronal differentiation and neurite extension of neuronal cells. Compound 14, one of the most active compounds, was used as a representative compound for mechanistic studies. Its action on neurite outgrowth was through phosphorylation/activation of multiple signaling molecules including Ca/calmodulin-dependent protein kinase II (CaMKII), extracellular signal-regulated kinase (ERK) and Akt. These findings collectively identify a new group of beneficial compounds for neuritogenesis, and may provide insights on drug discovery of neural repair and regeneration.

A Bivalent Securinine Compound SN3-L6 Induces Neuronal Differentiation via Translational Upregulation of Neurogenic Transcription Factors

“…Our previous findings showed that the ability of SN3-L6 in promoting neuronal differentiation is similar to retinoic acid (RA), a well-known neuronal morphogen for potent neural fate induction ( Tang et al, 2016 ). Here, we further compared more aspects of differentiation induced by SN3-L6 and RA, and we also included another widely used neuronal differentiation inducing factor dbcAMP for the comparison ( Figure 1B ).…”

“…We have shown that SN3-L6 is capable of inducing signaling changes at very early stages, i.e., ERK (extracellular-regulated kinase), Akt and calcium-dependent signaling activation was prominently evident at 15 min of treatment and lasted for up to 120 min ( Tang et al, 2016 ). This suggests that cellular reprogramming by SN3-L6 at early stages may be the key for differentiation induction.…”

“…SN3-L6 was synthesized as previously described and the purity was confirmed to be more than 98% by high-performance liquid chromatography (HPLC) ( Tang et al, 2016 ). RA and dbcAMP were purchased from Sigma-Aldrich (St. Louis, MO, United States); Puromycin was from Life Technologies; Minimum Eagle’s medium (MEM), DMEM/F12, fetal bovine serum (FBS), trypsin, penicillin-streptomycin, B-27 supplement, N2 supplement, bFGF and EGF were from Gibco; DNase I was from Roche Diagnostics.…”

“…We previously identified a securinine-derived compound, SN3-L6 (previously named compound 14 ), which exhibits potent activities toward neurite formation of neuronal cells ( Tang et al, 2016 ). Securinine is a natural compound that has long been suggested to have neuroexcitatory activities ( Beutler et al, 1985 ).…”

“…SN3-L6 possesses two moieties of securinine which linked by an N 1 ,N 6 -dipropyladipamide ( Figure 1A ). Preliminary mechanistic studies showed that treatment of SN3-L6 quickly leads to activation of a common set of signaling pathways involved in neuronal differentiation, such as those dependent on mitogen-activated protein kinase (MAPK) or protein kinase B (Akt) ( Tang et al, 2016 ). This suggests that SN3-L6 is capable of inducing rapid cellular changes for neuronal differentiation.…”