Skip to main content

DNA interaction of bromomethyl-substituted acridines

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.

This is a preview of subscription content, access via your institution.

Fig. 1
Scheme 1
Scheme 2
Fig. 2
Fig. 3
Fig. 4
Fig. 5

References

  • Ames BN, Lee FD, Durston WE (1973) An improved bacterial test system for the detection and classification of mutagens and carcinogens. Proc Natl Acad Sci USA 70:782–786

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Baguley BC, Denny WA, Atwell GJ, Cain BF (1981) Potential antitumor agents. 34. Quantitative relationships between DNA binding and molecular structure for 9-anilinoacridines substituted in the anilino ring. J Med Chem 24:170–177

    CAS  Article  PubMed  Google Scholar 

  • Bartoli S, Bazzicalupi C, Biagini S, Borsari L, Bencini A, Faggi E, Giorgi C, Sangregorio C, Valtancoli B (2009) Cu(II) complexation with an acridine-containing macrocycle. Assembly of water cluster chains within the cavity of tetranuclear metallomacrocycles. Dalton Trans 1223–1230

  • Basu AK, Marnett LJ, Romano LJ (1984) Dissociation of malondialdehyde mutagenicity in Salmonella typhimurium from its ability to induce interstrand DNA cross-links. Mutat Res 129:39–46

    CAS  Article  PubMed  Google Scholar 

  • Brown BR, Firt WJ, Yielding LW (1980) Acridine structure correlated with mutagenic activity in Salmonella. Mutat Res 72:373–388

    CAS  Article  PubMed  Google Scholar 

  • Brulikova L, Hlavac J, Hradil P (2012) DNA interstrand cross-linking agents and their chemotherapeutic potential. Curr Med Chem 19:364–385

    CAS  Article  PubMed  Google Scholar 

  • Chiron J, Galy J (2003) Reactivity of the acridine ring: One-pot regioselective single and double bromomethylation of acridine and some derivatives. Synlett 15:2349–2350

    Article  Google Scholar 

  • Demeunynck M, Charmantray F, Martelli A (2001) Interest of acridine derivatives in the anticancer chemotherapy. Curr Pharm Des 7:1703–1724

    CAS  Article  PubMed  Google Scholar 

  • Dimroth O, Criegee R (1957) Über Einige meso-substituierte dihydroacridine und ihre dehydrierungsprodukte. Chem Ber 90:2207–2215

    CAS  Article  Google Scholar 

  • Ehsanian R, Van Waes C, Feller SM (2011) Beyond DNA binding - a review of the potential mechanisms mediating quinacrine’s therapeutic activities in parasitic infections, inflammation, and cancers. Cell Commun Signal 9:13

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Gao C, Li B, Zhang B, Sun Q, Li L, Li X, Chen C, Tan C, Liu H, Jiang Y (2015) Synthesis and biological evaluation of benzimidazole acridine derivatives as potential DNA-binding and apoptosis-inducing agents. Bioorg Med Chem 23:1800–1807

    CAS  Article  PubMed  Google Scholar 

  • Gates KS (2009) An overview of chemical processes that damage cellular DNA: spontaneous hydrolysis, alkylation, and reactions with radicals. Chem Res Toxicol 22:1747–1760

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Hartley JA, Berardini MD, Souhami L (1981) An agarose gel method for the determination of DNA interstrand crosslinking applicable to the measurement of the rate of total and “second-arm” crosslink reactions. Anal Biochem 193:131–134

    Article  Google Scholar 

  • Haroun L, Ames BN (1981a) Mutagenicity of selected chemicals in the Salmonella/microsome mutagenicity test. In: De Serres F, Shelby MD (eds) Comparative chemical mutagenesis. Plenum Press, New York, NY, p 27–68.

    Chapter  Google Scholar 

  • Haroun L, Ames BN (1981b) The Salmonella mutagenicity test: an overview. In: Stich HF, San RHC (eds) Short-term tests for chemical carcinogens. Springer, New York, NY, p 108–119

    Chapter  Google Scholar 

  • Higashi T, Inami K, Mochizuki M (2008a) Synthesis and DNA-binding properties of 1,10-phenanthroline analogues as intercalating-crosslinkers. J Heterocycl Chem 45:1889–1892

    CAS  Article  Google Scholar 

  • Higashi T, Sakamoto M, Mochizuki M (2008b) Synthesis of acridine analogues as intercalating crosslinkers and evaluation of their potential anticancer properties. Heterocycles 75:1943–1952

    CAS  Article  Google Scholar 

  • Higashi T, Uemura K, Inami K, Mochizuki M (2009) Unique behavior of 2,6-bis(bromomethyl)naphthalene as a highly active organic DNA crosslinking molecule. Bioorg Med Chem 17:3568–3571

    CAS  Article  PubMed  Google Scholar 

  • Huang Y, Li L (2013) DNA crosslinking damage and cancer - a tale of friend and foe. Transl Cancer Res 2:144–154

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hurley LH (2002) DNA and its associated processes as targets for cancer therapy. Nat Rev Cancer 2:188–200

    CAS  Article  PubMed  Google Scholar 

  • Ishikawa S, Tajima M, Mochizuki M (2004) Synthesis and properties of bifunctional chloroalkyl nitrosamines with an intercalating moiety. Bioorg Med Chem 12:3791–3796

    CAS  Article  PubMed  Google Scholar 

  • Inami K, Ishikawa S, Mochizuki M (2009) Activation mechanism of N-nitrosodialkylamines as environmental mutagens and its application to antitumor research. Genes Environ 31:97–104

    CAS  Article  Google Scholar 

  • Ketron AC, Denny WA, Graves DE, Osheroff N (2012) Amsacrine as a topoisomerase II poison: importance of drug-DNA interactions. Biochemistry 51:1730–1739

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Löber G, Achtert G (1969) On the complex formation of acridine dyes with DNA. VII. Dependence of the binding on the dye structure. Biopolymers 8:595–608

    Article  PubMed  Google Scholar 

  • Louie AC, Issell BF (1985) Amsacrine (AMSA)-a clinical review. J Clin Oncol 3:562–592

    CAS  Article  PubMed  Google Scholar 

  • Nitiss JL (2009) Targeting DNA topoisomerase II in cancer chemotherapy. Nat Rev Cancer 9:338–350

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Noll DM, Mason TM, Miller PS (2006) Formation and repair of interstrand cross-links in DNA. Chem Rev 106:277–301

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Maron DM, Ames BN (1983) Revised methods for the Salmonella mutagenicity test. Mutat Res 113:173–215

    CAS  Article  PubMed  Google Scholar 

  • Mortelmans K, Zeiger E (2000) The Ames Salmonella/microsome mutagenicity assay. Mutat Res 455:29–60

    CAS  Article  PubMed  Google Scholar 

  • Sakore TD, Jain SC, Tsai C, Sobell HM (1977) Acridine: 5-iodocytidylyl- (3’-5’)guanosine crystalline complex. Proc Natl Acad Sci USA 74:188–192

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Sasikala WD, Mukherjee A (2013) Intercalation and de-intercalation pathway of proflavine through the minor and major grooves of DNA: roles of water and entropy. Phys Chem Chem Phys 15:6446–6455

    CAS  Article  PubMed  Google Scholar 

  • Schmidt A, Liu M (2015) Chapter Four – Recent Advances in the Chemistry of Acridines. Adv Heterocycl Chem 115:287–353

    CAS  Article  Google Scholar 

  • Shieh HS, Berman HM, Dabrow M, Neidle S (1980) The structure of drug-deoxydinucleoside phosphate complex; generalized conformational behavior of intercalation complexes with RNA and DNA fragments. Nucleic Acids Res 8:85–97

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Su T, Lin Y, Chou T, Zhang X, Bacherikov VA, Chen C, Liu LF, Tsai T (2006) Potent antitumor 9-anilinoacridines and acridines bearing an alkylating N-mustard residue on the acridine chromophore: synthesis and biological activity. J Med Chem 49:3710–3718

    CAS  Article  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Keiko Inami.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

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

Keywords

  • Acridine
  • Halomethyl group
  • Crosslink
  • Intercalation
  • Mutagenicity