ABSTRACT
We report a potent cationic lipid, SST-02 ((3-hydroxylpropyl)dilinoleylamine), which possesses a simple chemical structure and is synthesized just in one step. Cationic lipids are key components of siRNA-lipid nanoparticles (LNP), which may serve as potential therapeutic agents for various diseases. For a decade, chemists have given enhanced potency and new functions to cationic lipids along with structural complexity. In this study, we conducted a medicinal chemistry campaign pursuing chemical simplicity and found that even dilinoleylmethylamine (SST-01) and methylpalmitoleylamine could be used for the in vitro and in vivo siRNA delivery. Further optimization revealed that a hydroxyl group boosted potency, and SST-02 showed an ID50 of 0.02 mg/kg in the factor VII (FVII) model. Rats administered with 3 mg/kg of SST-02 LNP did not show changes in body weight, blood chemistry, or hematological parameters, while the AST level decreased at a dose of 5 mg/kg. The use of SST-02 avoids a lengthy synthetic route and may thus decrease the future cost of nucleic acid therapeutics.
ABSTRACT
Total synthesis of the biologically important axane sesquiterpenes, gleenol (1) and axenol (2), was accomplished through a readily available spiro[4.5]decane. The key features of the synthesis of 1 and 2 include Claisen rearrangement to afford the multi-functionalized spiro[4.5]decane 4 as a single diastereomer in excellent yield, installation of the C7 isopropyl group via ketene dithioacetal instead of direct alkylation and a diastereoselective reduction of ketone under the Birch conditions.
