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Synthesis and in vitro anticancer evaluation of 1,8-naphthalimide N(4) and S(4)-derivatives combining DNA intercalation and alkylation capabilities

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Abstract

Research on DNA binding antitumor agents has been classically steered by either non-covalent (DNA intercalation) or covalent (DNA alkylation) interactions. In this context bi-functional anticancer molecules are particularly attractive since they are capable of sequential DNA intercalation followed by DNA alkylation. Here we describe the synthesis and in vitro anticancer activity of bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives. Cell viability assays indicate that our amonafide-N-mustard chimeras are selective, effective only on certain tumor cell lines, and less toxic toward non-malignant cells than the drug amonafide. The biological activities of the bi-functional derivatives presented here are encouraging and the compounds are suitable for further optimization and in vivo studies.

Graphical Abstract

Here we describe the synthesis and in vitro anticancer activity of three bi-functional 1,8-naphthalimide N(4) and S(4)-derivatives presenting both DNA intercalation and alkylation capabilities. Cell viability assays indicate that these amonafide-N-mustard chimeras are effective only on certain tumor cell lines and are less toxic towards non-malignant cells than their parent drug: amonafide.

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Acknowledgments

The authors thank Dr. Hugo Gottlieb from Bar-Ilan University for NMR experiments and helpful advice. The work was supported by the Authority for Research & Development of Ariel University, the Israel Cancer Association grant no. 20150910 (Gerlitz lab.) and the Israel Cancer Research Fund (Gerlitz Lab).

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Authors and Affiliations

  1. Department of Biological Chemistry, Ariel University, 40700, Ariel, Israel

    Tamara Brider, Boris Redko, Gary Gellerman & Flavio Grynszpan

  2. Department of Molecular Biology, Ariel University, 40700, Ariel, Israel

    Adi Cohen-Matzlich & Gabriel Gerlitz

  3. The Advanced Technologies Center, Sheba Medical Center, 52621, Tel Hashomer, Israel

    Mor Oron-Herman

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  1. Tamara Brider
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  2. Boris Redko
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  3. Mor Oron-Herman
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  5. Gabriel Gerlitz
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Correspondence to Gary Gellerman or Flavio Grynszpan.

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11164_2015_2115_MOESM1_ESM.pdf

Supplementary data (selected calibration curves and kinetic data, MS, 1H and 13C NMR spectra) associated with this work can be found in the online version at DOI. (PDF 1041 kb)

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Brider, T., Redko, B., Oron-Herman, M. et al. Synthesis and in vitro anticancer evaluation of 1,8-naphthalimide N(4) and S(4)-derivatives combining DNA intercalation and alkylation capabilities. Res Chem Intermed 42, 1741–1757 (2016). https://doi.org/10.1007/s11164-015-2115-1

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