Novel Prenylated Indole Alkaloids with Neuroprotection on SH-SY5Y Cells against Oxidative Stress Targeting Keap1–Nrf2

Abstract

Oxidative stress has been implicated in the etiology of Parkinson’s disease (PD). Molecules non-covalently binding to the Keap1–Nrf2 complex could be a promising therapeutic approach for PD. Herein, two novel prenylated indole alkaloids asperpenazine (1), and asperpendoline (2) with a scarce skeleton of pyrimido[1,6-a]indole were discovered from the co-cultivated fungi of Aspergillus ochraceus MCCC 3A00521 and Penicillium sp. HUBU 0120. Compound 2 exhibited potential neuroprotective activity on SH-SY5Y cells against oxidative stress. Molecular mechanism research demonstrated that 2 inhibited Keap1 expression, resulting in the translocation of Nrf2 from the cytoplasm to the nucleus, activating the downstream genes expression of HO-1 and NQO1, leading to the reduction in reactive oxygen species (ROS) and the augment of glutathione. Molecular docking and dynamic simulation analyses manifested that 2 interacted with Keap1 (PDB ID: 1X2R) via forming typical hydrogen and hydrophobic bonds with residues and presented less fluctuation of RMSD and RMSF during a natural physiological condition.

Marine natural products

“…149) and cyclic tripeptide 352, 150 whilst co-cultivation of deep sea-derived A. ochraeus with a terrestrial soil-derived Penicillium yielded prenylated indole alkaloids 353 and 354 . 151 Aspergillus strains derived from deep-sea sediment yielded a variety of metabolites including phenols 355 , 356 (C-8 epimers), 357 , 358 , 152 aromatic polyketides 359 – 361 and isoquinoline alkaloids 362 , 363 , 153 364 – 377 , 154 acremolin alkaloid 378 , 155 and cyclopropane acids 379 – 382 . 156 Sponge-derived strains were the source of 2,5-diketopiperazines 383 – 385 , 157 isocoumarin 386 , propylpyridinium anthraquinone 387 , resorcinol derivative 388 , 158 and dipyrroloquinones 389 , 390 , 159 whilst notoamide alkaloids 391 – 396 , 160 prenylated notoamide-type alkaloids 397 – 406 , 161 butenolides 407 – 411 and p -hydroxybenzaldehyde derivative 412 (ref.…”

NRF2 Activation by Nitrogen Heterocycles: A Review

“…Prenylated indole alkaloid ( 26 ) ( Table 2 ) also exerts neuroprotection against oxidative stress in SH-SY5Y cells via the nuclear translocation of NRF2 and the induction of NQO1 and HO-1. It activates NRF2 signaling by binding non-covalently with KEAP1, resulting in the reduction of ROS accumulation and the enhancement of the GSH level [ 117 ]. An indole analogue bearing a lactic acid moiety ( 27 ) ( Table 2 ) attenuates inflammation and protects intestinal epithelial cells via the activation of NRF2 and aryl hydrogen receptor pathways [ 118 ].…”

Emerging Role of Plant-Based Bioactive Compounds as Therapeutics in Parkinson’s Disease

“…Several studies have demonstrated a neuroprotective effect of alkaloids against H 2 O 2induced oxidative damage in SH-SY5Y cell lines and AChE inhibitory activity [211,212]. Studies conducted in vivo subjected to aluminum-induced neuroinflammation and excitotoxicity have revealed that alkaloid therapy was successful in controlling glutamate and acetylcholinesterase levels, which were otherwise raised by aluminum.…”