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DNA interaction of bromomethyl-substituted acridines

Medicinal Chemistry Research volume 26, pages 3375–3383 (2017)Cite this article

Abstract

A series of acridines with bifunctional substituents was synthesized with the dual properties of DNA alkylation and intercalation. 4,5-Bis(bromomethyl)acridine (1) was previously reported to crosslink and intercalate with DNA. In this study, 1,8-bis(bromomethyl)acridine (2) and 2,7-bis(bromomethyl)acridine (3), monofunctional 2-(bromomethyl)-7-methylacridine (4) and 2,7-dimethylacridine (5) were synthesized, and their crosslinking and intercalative activities were investigated to assess the reactivity of bromomethyl acridines with DNA. Interstrand crosslinking activity was similar among the three bis(bromomethyl)acridines. The acridines exhibited intercalation activity for calf thymus DNA as follows: 3 > 4 > 2 = 1 >>> 5. Intracellular DNA-crosslinking and DNA-intercalating activities were evaluated using the Ames assay. 4 was mutagenic in Salmonella typhimurium TA100 and TA98, indicating that the bromomethyl group alkylated DNA bases. All three bis(bromomethyl)acridines were mutagenic in S. typhimurium TA92 and TA94, which can detect intracellular crosslinking DNA damage, whereas 5 was not mutagenic in these strains. The results showed that the bis(bromomethyl)acridines crosslinked DNA and intercalated between DNA bases, and 3 exhibited the highest crosslinking and intercalating activity.

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Acknowledgements

This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by a Grant-in-Aid for the Science Research Promotion Fund from the Japan Private School Promotion Foundation.

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Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, Tokyo University of Science, Yamazaki 2641, Noda-shi, Chiba, 278-8510, Japan

    Kazuya Harada, Takahiro Imai, Masataka Mochizuki & Keiko Inami

  2. Faculty of Pharmacy, Keio University, Shibakoen 1-5-30, Minato-ku, Tokyo, 105-8512, Japan

    Junko Kizu

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  1. Kazuya Harada
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  2. Takahiro Imai
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  3. Junko Kizu
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  4. Masataka Mochizuki
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  5. Keiko Inami
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Correspondence to Keiko Inami.

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Harada, K., Imai, T., Kizu, J. et al. DNA interaction of bromomethyl-substituted acridines. Med Chem Res 26, 3375–3383 (2017). https://doi.org/10.1007/s00044-017-2030-7

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  • DOI: https://doi.org/10.1007/s00044-017-2030-7

Keywords

  • Acridine
  • Halomethyl group
  • Crosslink
  • Intercalation
  • Mutagenicity