Synthesis of lipophilic sila derivatives of N‐acetylcysteineamide, a cell permeating thiol

Abstract

N-acetyl-L-cysteine (L-NAC) is a potent antioxidant that can reduce levels of reactive oxygen species. N-acetyl-cysteine-amide, the amide form of L-NAC, has recently been reported to be more lipophilic and permeable through cell membranes than NAC, and to be able to traverse the blood-brain barrier. In this communication we report the synthesis and characterization of highly lipophilic sila-amide derivatives of L-NAC that may show enhanced cell penetration and bioavailability.

Organosilicon Molecules with Medicinal Applications

“…West has reported silicon-derivatives of N-acetylcysteineamide 14 (NACA, AD4), an amide derivative of N-acetyl-Lcysteine ( 16), which is a powerful antioxidant and a precursor to glutathione. 30 The more lipophilic amide derivative 14 is known to be a better radical scavenger than N-acetyl-L-cysteine and is capable of crossing the blood−brain barrier, making it relevant for therapeutic applications for Alzheimer's disease, Parkinson's disease, and multiple sclerosis. The authors propose that sila-amide derivatives such as 15 will further enhance the lipophilicity, and these derivatives are expected to be useful in optimizing the pharmacokinetic properties.…”

2-[3-(Methyldiphenylsilyl)propyl]isoindoline-1,3-dione

“…For literature related to drug design see: Bains & Tacke (2003); Gately & West (2007); Guzei et al (2010a,b); Lee et al (1996); Tsuge et al (1985); Yoon et al (1991); Zakai et al (2010). For a description of the Cambridge Structural Database, see: Allen (2002).…”

“…It is a congener of 2-(((4-methoxyphenyl)dimethylsilyl)methyl)isoindoline-1,3-dione (Guzei et al, 2010a) and 2-(2-(trimethylsilyl)ethyl)isoindoline-1,3-dione (Guzei et al, 2010b) recently reported by us. These sila amines were subsequently coupled with a selection of pharmaceutical agents containing a carboxylic acid, including indomethacin and N-acetyl L-cysteine (Zakai et al, 2010) as part of our continuing efforts at drug repurposing (Gately & West, 2007) using silicon chemistry (Bains & Tacke, 2003).…”

Hydrogen bond and internal rotations barrier: DFT study on heavier group-14 analogues of formamide

“…Formamide 1 had attracted much interest to characterize its fundamental properties for the last two decades since it is the simplest species containing the amide linkage (–CO–NH–), which is a pharmacophore of the antibacterial agents and designed enzyme inhibitors . Recent reports for organosilicon chemistry showed that silicon substitution can improve bio‐activity of drug derivative by modifying their selectivity, metabolization rate and tissue distribution since silicon slightly differs from carbon in atomic size, electronegativity and lipophilicity . This prompts us to probe the properties of formamide substituted by heavier group‐14 elements for possible application of heavier group‐14 formamide in drug design.…”