Investigations into neuroprotectivity, stability, and water solubility of 7‐O‐cinnamoylsilibinin, its hemisuccinate and dehydro derivatives

Abstract

Derivatives of the recently described potent neuroprotective 7-O-cinnamoylsilibinin ester were prepared: its hemisuccinate to improve water solubility and the dehydrosilibinin ester that was shown to form in assay media to investigate its role in overall neuroprotective effects. 7-O-Cinnamoyl-2,3-dehydrosilibinin is less neuroprotective than 7-O-cinnamoylsilibinin in a murine hippocampal cell line (HT-22) andwe conclude that the dehydrosilibinin derivatives are not the actual carriers of neuroprotective properties, at least in the assay applied. Solubility of the test compounds was determined in shake-flask experiments and the ester's solubility was greatly improved by introduction of a hemisuccinate at the 23-position of silibinin.Time-stability curves in assay media were recorded. The hemisuccinate ester did not act as a prodrug to release 7-O-cinnamoylsilibinin but is the second ester bond to be cleaved. Nevertheless, it still exhibits significant neuroprotection. Therefore, its greatly increased solubility might effectively counterbalance lower in vitro neuroprotection. K E Y W O R D S2,3-dehydrosilibinin, neuroprotection, silibinin, solubility, succinate

Sterubin: Enantioresolution and Configurational Stability, Enantiomeric Purity in Nature, and Neuroprotective Activity in Vitro and in Vivo

“…HT22 cells are a murine hippocampal nerve cell line. They are sensitive to oxidative glutamate toxicity (oxytosis) due to a lack of ionotropic glutamate receptors . Addition of high concentrations of extracellular glutamate inhibits the transport of cystine, the oxidized form of cysteine, via the cystine/glutamate antiporter, which results in glutathione (GSH) depletion.…”

“…have shown a remarkable increase in potency of both flavonoids and flavonolignan derivatives, in vitro and in vivo, by esterification of the hydroxy group at C‐7 with phenolic acids. The resulting esters, however, suffer from poor water solubility and high molecular weight …”

Dual-Acting Cholinesterase–Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo

“…For the biological evaluation of compound 8 regarding its effects on murine hippocampal neurons (HT-22), we performed a glutamate assay as previously described. , This neuronal cell line is derived from murine hippocampal tissue and is glutamate sensitive . HT-22 cells lack ionotropic glutamate receptors.…”

7-O-Esters of taxifolin with pronounced and overadditive effects in neuroprotection, anti-neuroinflammation, and amelioration of short-term memory impairment in vivo

“…Flavonolignan-based silibinin-esters with phenolic acids suffer from some drawbacks. The high molecular weight of the compounds and their constrained solubility counteract their drugability [13]. The secondary plant metabolite taxifolin is a flavonoid, structurally closely related to silibinin, but smaller in size (Fig.…”