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Development of oxopyrrolidine-based anti-cancer compounds: DNA binding, in silico, cell line studies, drug-likeness and mechanism at supra-molecular level

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Abstract

Due to an increasing demand for effective anti-cancer drugs, an oxopyrrolidine-based ligand, sodium 1-(3-(2-aminoethylamino)propyl)-5-oxopyrrolidine-2-carboxylate, was synthesised by the sodium hydride-assisted coupling of pyroglutamic acid with 1,3-diiodopropane under a nitrogen atmosphere. The intermediate thus formed was allowed to react with ethylenediamine in acetonitrile. The ligand formed individual complexes with Cu(II) and Ni(II) metal ions, respectively. The complexes were relatively resistant to degradation in PBS at physiological pH. The DNA-binding constants (K b) for the ligand, copper and nickel complexes were 2.09 × 104 M-1, 2.37 × 104 M-1 and 2.11 × 104 M-1, respectively, revealing the strong binding of these complexes with DNA. Haemolysis assays indicated that the ligand and its complexes were less toxic to rabbit RBCs than doxorubicin. Lipinski’s parameters calculated for the reported compounds indicated their good oral bioavailability. All the compounds exhibited good activities towards MCF-7 (wild type) cancer cell lines. The results of in silico studies, DNA-binding and anti-cancer activities indicated that the reported compounds might be interacting with DNA as one of their possible mechanisms of action.

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  1. Department of Chemistry, Jamia Millia Islamia (Central University), New Delhi, 10025, India

    Imran Ali, Waseem A. Wani & Kishwar Saleem

  2. Department of Biomedical Engineering, Chung Yuan Christian University, 200, Chung Pei Rd., Chung Li, 32023, Taiwan

    Ming-Fa Hsieh

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Ali, I., Wani, W.A., Saleem, K. et al. Development of oxopyrrolidine-based anti-cancer compounds: DNA binding, in silico, cell line studies, drug-likeness and mechanism at supra-molecular level. Chem. Pap. 68, 540–552 (2014). https://doi.org/10.2478/s11696-013-0486-6

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