Design, synthesis and evaluation of a novel π–π stacking nano-intercalator as an anti-tumor agent

MedChemComm
2015.0

Abstract

Based on the knowledge that cyclohexane-1,4-dione, piperazine and β-carboline are the essential building blocks of DNA intercalators, β-carboline-3-carboxylic acid is a π-π stacking like DNA intercalator, and β-carboline derivatives can form nanoparticles, this paper hypothesized that (2'S,5'S)-tetrahydropyrazino[1',2':1,6] di{2,3,4,9-tetra-hydro-1H-pyrido[3,4-b]indole}-1',4'-dione (THPDTPI) would be a π-π stacking lead nano-intercalator. The docking investigation explored that THPDTPI can intercalate into DNA with a π-π stacking manner. The simple condensation of 3S-1,2,3,4-tetra-hydro-β-carboline-3-carboxylic acid provided THPDTPI in good yield and high purity. The TEM, SEM and AFM imaging visualized that THPDTPI formed nanoparticles in ultrapure water, in solid state and in rat plasma. Faraday-Tyndall effect proved that THPDTPI exhibited nano-properties in pH 2.0 and pH 7.0 water. Spectrophotometric assays suggested that the interaction model of THPDTPI and CT DNA was π-π stacking intercalation. In vivo THPDTPI dose-dependently slowed the tumor growth of S180 mice with a minimal effective dose of 0.01 µmol/kg/day. In vitro THPDTPI exhibited anti-proliferation activities on S180 and Hela cells with IC50 values of 0.39 and 3.5 µM, respectively. Even when the single dose was raised up to 10000 folds of the minimal effective dose, i.e. 100µmol/kg, THPDTPI still did not show liver, kidney and systematic toxicity in mice. These findings provide a strategy for designing THPDTPI like π-π stacking nano-intercalators.

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