Z16b, a natural compound from Ganoderma cochlear is a novel RyR2 stabilizer preventing catecholaminergic polymorphic ventricular tachycardia

Insights into Ganoderma fungi meroterpenoids opening a new era of racemic natural products in mushrooms

“…22,39,40 It was proposed as a racemic mixture from G. cochlear in the later study of its biological activity on catecholaminergic polymorphic ventricular tachycardia (CPVT), and the absolute stereochemistry of the two enantiomers was also proposed. 41,42 Fornicin A (24) with R configuration possessed the ability of inhibition on Ca 2+ spark frequency (CaSF) in R2474S/+ cardiomyocytes, abnormal postpacing Ca 2+ release. 41 (±)-Ganocapenoid D (29 and 30), with significant ABTS radical scavenging activity, moderate DPPH radical scavenging activity, and moderate neurite outgrowth-promoting activity, were generated from G. capense and G. oregonense, and were proposed absolute stereochemistry by CD comparisons.…”

“…41,42 Fornicin A (24) with R configuration possessed the ability of inhibition on Ca 2+ spark frequency (CaSF) in R2474S/+ cardiomyocytes, abnormal postpacing Ca 2+ release. 41 (±)-Ganocapenoid D (29 and 30), with significant ABTS radical scavenging activity, moderate DPPH radical scavenging activity, and moderate neurite outgrowth-promoting activity, were generated from G. capense and G. oregonense, and were proposed absolute stereochemistry by CD comparisons. 43,44 The investigation of G. oregonense also resulted in the isolation of (±)-oregonensins A and B (25)(26)(27)(28), chizhine E (31 and 32) and applanatumol U (33 and 34), and these compounds were developed significant ABTS radical scavenging and moderate DPPH radical scavenging activities.…”

“…46 Another racemic analog, lucidulactone B (39 and 40), was found in the study of G. lucidum and G. applanatum, and has not been elucidated the absolute configurations. 47,48 Cochlearin F (41), (±)-ganodercin W (42 and 43), and ganocapenoid C (44) which possess a benzofuran moiety, were generated from G. cochlear (41)(42)(43) and G. capense (44). 35,43 Cochlearin F (41) possessed the ability of antioxidation.…”

“…26 Monoterpenes and sesquiterpenes have been found relatively common as racemates 25 ; therefore it is reasonable to consider meroterpenoids which consist of monoterpenes or sesquiterpenes might be racemic. Chiral analysis on GMs has not been materialized until the reporting of the foremost racemate lingzhiol, and many have been found racemic in later research, including, fornicins A-C (23 and 24, 274 and 275, 253 and 254), 37,41,52 ganomycin I (284 and 285), 37,56 ganoresinain B (280 and 281), 52 ganoduriporols A and B (582-585), 49 lucidimine C (665 and 666), 116 and sinensine E (671 and 672). 116 Meanwhile, some GMs are known to be optically pure in one Ganoderma species but racemic or scalemic in another, such as lingzhiol (135 and 136) (racemic in G. lucidum and optically pure in G. australe), 3,52 spiroganodermaine D (177 and 178) (scalemic in G. lucidum and optically pure in G. australe), 71 applanatum and optically pure in G. sinense), 38,62 ganotheaecolumols A and B (406-409) (racemic in G. australe and optically pure in G. theaecolum), 45,52 ganomycin E (255 and 256) (racemic in G. lucidum and G. capense, and optically pure in G. australe), 52,75,79 lingzhines E and F (58-61) (racemic in G. lingzhi, and optically pure in G. lucidum and G. australe), [50][51][52] and dayaolingzhiol H (257 and 258) (racemic in G. petchii and optically pure in G. lucidum).…”

Structural Insight Into Ryanodine Receptor Channelopathies

“…Furthermore this compound also showed good efficacy against CPVT in human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) carrying the R176Q mutation ( Word et al, 2021 ). In addition, Wan et al 2(2022) . reported the discovery that a natural product, Z16b, isolated from Ganoderma cochlear , has a potent therapeutic effect on CPVT.…”