Inhibition of Neuroinflammation by Synthetic Androstene Derivatives Incorporating Amino Acid Methyl Esters on Activated BV‐2 Microglia

Abstract

Androstene derivatives incorporating amino acid methyl esters were prepared, and their anti-inflammatory effects were evaluated in lipopolysaccharide (LPS)-activated BV-2 microglial cells. Several compounds exhibited dose-dependent inhibition. The most active compound, methyl ((3S,10R,13S)-3-hydroxy-10,13-dimethyl-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-17-carbonyl)-L-phenylalaninate (10) significantly suppressed LPS-induced expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α). Mechanistic studies revealed that compound 10 markedly inhibits phosphorylation of p38 mitogen-activated protein kinases (MAPKs) and subsequent transcription factor (NF-κB) and activator protein-1 (AP-1) activation. Furthermore, compound 10 decreased LPS-activated microglial neurotoxicity in a condition medium/HT-22 neuroblastoma co-culture model. Taken together, these results suggest 10 is a potential lead compound for the development of a novel therapeutic agent for neurodegenerative diseases.

Suppression of Inflammation Delays Hair Cell Regeneration and Functional Recovery Following Lateral Line Damage in Zebrafish Larvae

“…BRS-28 is a derivative of 5α-cholestan-6-one, which has been confirmed to be a remarkable suppressor of the production of pro-inflammatory factors in a dose-dependent manner. It is reported that these compounds can significantly inhibit LPS-induced JNK and p38 phosphorylation and suppress the production of NO, TNF-α, IL-1β, cox-2, and iNOS [ 37 , 46 , 47 ]. Additionally, BRS-28 inhibits the production of pro-inflammatory factors, thereby further reducing macrophage activation.…”

Accessible Method for the Development of Novel Sterol Analogues with Dipeptide-like Side Chains That Act as Neuroinflammation Inhibitors

“…This compound is a synthetic 5α-cholestan-6-one sterol analogue that inhibits the microglia-mediated inflammatory response by blocking the increase in the production of NO, IL-1β, and TNF-α and reducing infarction volume in a focal ischemic mouse model . Recently, we have also reported that an androstene-sterol derivative, compound 2 , exhibited a higher antineuroinflammatory potency than compound 1 . As part of our ongoing sterol neuroinflammation inhibitor discovery and development program, we are interested in the generation of sterol scaffolds with dipeptide-like side chains using a simple and fast procedure, Ugi four-component condensation (U-4CC), in which an aldehyde, an amine, a carboxylic acid, and an isocyanide react together to give α-aminoacyl amide derivatives. − U-4CC is one of the most well-known and efficient multicomponent reactions and is widely used in medicinal chemistry.…”