Carbon-silicon switch led to the discovery of novel synthetic cannabinoids with therapeutic effects in a mouse model of multiple sclerosis

Sila-CBD Derivatives as Inhibitors of Heme-Induced NLRP3 Inflammasome: Application in Hemolytic Diseases

“…Toward this, the condensation of (+)-(1S,4R)-p-mentha-2,8-dien-1-ol ( 16) with compounds 11a−11c in the presence of p-TSA gave compounds 14a− 14c. 40 We also confirmed the absolute stereochemistry of compound 14a with the help of X-ray crystallography data (CCDC 2295244), Scheme 2 (see SI for additional information). These compounds were further subjected to oxidation by using SIBX 45 to deliver silylated quinone cannabidiol derivatives 15a−15c (Scheme 2).…”

“…As planned, we started the synthesis of sila-CBG with varying n -alkyl silyl groups attached to the benzene ring (Scheme ). The required starting materials 11a – 11c (sila-olivetol derivatives) were prepared from 1-bromo-3,5-dimethoxy benzene by a lithiation/silylation/demethylation sequence . The sila-olivetol derivatives on reaction with geraniol in the presence of the catalytic amount of p -TSA ( p -toluenesulfonic acid) delivered the sila-CBG analogues 12a – 12c in moderate yield.…”

“…The required starting materials 11a−11c (silaolivetol derivatives) were prepared from 1-bromo-3,5-dime- thoxy benzene by a lithiation/silylation/demethylation sequence. 40 The sila-olivetol derivatives on reaction with geraniol in the presence of the catalytic amount of p-TSA 44 (ptoluenesulfonic acid) delivered the sila-CBG analogues 12a− 12c in moderate yield. sila-CBGs on oxidative dearomatization using the SIBX (stabilized 2-iodoxybenzoic acid) reagent 45 afforded the silylated quinone cannabigerol derivatives 13a− 13c in 24 to 33% yields.…”

“…Previously, we have shown that silicon analogues of the oxazolidinone antibiotic linezolid displayed an improved CNS penetration . One common denominator among synthetic cannabinoids is a phenyl/quinone moiety with a gem -dimethyl substituted tail group (Figure b) , which could be replaced by a dimethyl-substituted silyl group. Such a modification was expected to maintain the potency of cannabinoid derivatives and lead to novel compounds with improved drug-like properties.…”

“…Initially, we designed and synthesized gem -dimethyl analogues of sila-CBD ( 14a – 14c ) to check its potential for neurological disorders. While we were working on this project, a related study published by Cheng’s group disclosed silicon analogues of cannabinoids (sila-CBD) with improved pharmacokinetic profiles and therapeutic effects in a mouse model of multiple sclerosis . Consequently, based on the reported activity of CBD against the NLRP3 inflammasome, we decided to explore these compounds against heme-mediated induction of the NLRP3 inflammasome, which is an unexplored area.…”