Derivatives of caffeic acid, a natural antioxidant, as the basis for the discovery of novel nonpeptidic neurotrophic agents

• Published in: Bioorganic & medicinal chemistry 2017-06, Vol.25 (12), p.3235-3246
• Main Authors: Moosavi, Fatemeh, Hosseini, Razieh, Rajaian, Hamid, Silva, Tiago, Magalhães e Silva, Diogo, Saso, Luciano, Edraki, Najmeh, Miri, Ramin, Borges, Fernanda, Firuzi, Omidreza
• Format: Article
• Language: English
• Subjects: AKT; Animals; Antioxidants - chemistry; Antioxidants - pharmacology; Caffeic Acids - chemistry; Caffeic Acids - pharmacology; Caffeic amides; Cell signaling; Cell Survival - drug effects; ERK1/2; MAP Kinase Signaling System - drug effects; Neurogenesis - drug effects; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neurotrophic agents; PC12 Cells; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Rats; Signal Transduction - drug effects
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2017.04.026

Synthesized alkyl amides of caffeic acid induce cell differentiation and increase survival in PC12 neuronal cells at 25µM. These neurotrophic effects seem to be mediated by activation of ERK1/2 and AKT signaling pathways, but not by direct TrkA phosphorylation. [Display omitted] •A series of caffeic amides with variable alkyl chain lengths were synthesized.•Synthesized amides increased cell survival and NGF-induced neurite outgrowth in PC12.•The neurotrophic effects were mediated by activation of ERK1/2 and AKT signaling.•Interaction with PI3K and drug likeness were studied. Neurodegenerative disorders, such as Parkinson’s disease and Alzheimer’s disease, threaten the lives of millions of people and the number of affected patients is constantly growing with the increase of the aging population. Small molecule neurotrophic agents represent promising therapeutics for the pharmacological management of neurodegenerative diseases. In this study, a series of caffeic acid amide analogues with variable alkyl chain lengths, including ACAF3 (C3), ACAF4 (C4), ACAF6 (C6), ACAF8 (C8) and ACAF12 (C12) were synthesized and their neurotrophic activity was examined by different methods in PC12 neuronal cells. We found that all caffeic acid amide derivatives significantly increased survival in PC12 neuronal cells in serum-deprived conditions at 25μM, as measured by the MTT assay. ACAF4, ACAF6 and ACAF8 at 5µM also significantly enhanced the effect of nerve growth factor (NGF) in inducing neurite outgrowth, a sign of neuronal differentiation. The neurotrophic effects of amide derivatives did not seem to be mediated by direct activation of tropomyosin receptor kinase A (TrkA) receptor, since K252a, a potent TrkA antagonist, did not block the neuronal survival enhancement effect. Similarly, the active compounds did not activate TrkA as measured by immunoblotting with anti-phosphoTrkA antibody. We also examined the effect of amide derivatives on signaling pathways involved in survival and differentiation by immunoblotting. ACAF4 and ACAF12 induced ERK1/2 phosphorylation in PC12 cells at 5 and 25µM, while ACAF12 was also able to significantly increase AKT phosphorylation at 5 and 25µM. Molecular docking studies indicated that compared to the parental compound caffeic acid, ACAF12 exhibited higher binding energy with phosphoinositide 3-kinase (PI3K) as a putative molecular target. Based on Lipinski’s rule of five, all of the compounds obeyed three molecular descriptors (HBD, HBA