Synthesis, characterization, and antitumor activity of rare earth metal complexes of benzoic acid nitrogen mustard
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Med Chem Res (2013) 22:2862–2869 DOI 10.1007/s00044-012-0286-5
ORIGINAL RESEARCH
Synthesis, characterization, and antitumor activity of rare earth metal complexes of benzoic acid nitrogen mustard Sufeng Zhou • Yun Fu • Xizhi Fan Yanfang Zhang • Changzheng Li
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Received: 21 March 2012 / Accepted: 20 October 2012 / Published online: 2 November 2012 Ó Springer Science+Business Media New York 2012
Abstract Benzoic acid nitrogen mustard and its rare earth metal complexes were synthesized and characterized by elemental analyses, IR, electronic spectrum, and EPR. The interaction of synthesized complexes with Ct-DNA was investigated and reviewed as a mixed manner of both intercalation and alkylation via fluorescence titration. Their biological activities were also evaluated in K562 and Vero cell lines, indicating that complexes had a significant inhibitory effect; however, there was no synergistic effect instead of antagonistic effect compared to benzoic acid nitrogen mustard. The possible mechanism through cellular apoptosis was also explored by comet assay. Keywords Benzoic acid nitrogen mustard Synthesis Antitumor activity Rare earth metal complex Comet assay
Introduction Nitrogen mustard is one of the most useful drugs in cancer chemotherapy, lack of selectivity and its toxic-side effect as well as resulting drug-resistance, carcinogenesis, and Y. Fu Y. Zhang C. Li (&) Department of Molecular Biology & Biochemistry, Xinxiang Medical University, Xinxiang 453003, Henan, People’s Republic of China e-mail: [email protected] S. Zhou Clinical Skill Training Center, Xinxiang Medical University, Xinxiang 453003, Henan, People’s Republic of China X. Fan Department of Computer, Xinxiang Medical University, Xinxiang 453003, Henan, People’s Republic of China
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mutation, make its applications limited. In order to improve its antitumor activity, many of its derivatives have been synthesized; melphalan, cyclophosphamide, bendamustine, and chlorambucil are good examples and have been widely used in clinic (Leoni et al., 2008). Among massive derivatives of nitrogen mustard, benzoic acid nitrogen mustard (BANM) is effective against quiescent cell and tend to be less susceptible to induced resistance than most anticancer drugs, thereby its different derivatives were reported in many literatures (Beria and Nesi, 2002; Koutsourea et al., 2008). In addition to its good fluorescence and noncell-cycle-specific feature, BANM is widely used in prodrug design (Roger and Roger, 1996), such as antibody-directed enzyme prodrug therapy, which is designed to deliver it to a given site. It is well known that rare earth metal is an important chemical element and has significant biological feature. Rare earth metal complexes have been widely used as diagnosis reagent for pathological changes of lung, brain, and kidney (Zhou et al., 2010). Some complex has ability to promote blood circulation and protect cells from radiation damage (Gschneidner et al., 1999). In addition, the rare earth metal complexes have not been shown to have
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