Skip to main content
NCBI home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1996 Jan 15;24(2):311–315. doi: 10.1093/nar/24.2.311

Backbone and benzoyl mustard carrying moiety modifies DNA interactions of distamycin analogues.

A Ciucci 1, S Manzini 1, P Lombardi 1, F Arcamone 1
PMCID: PMC145640  PMID: 8628655

Abstract

Alkylating distamycin derivative FCE-24517 (l) is the prototype of a novel class of alkylating agents. In the present study we have investigated the effect of further chemical modifications introduced in the alkylating distamycin-derived molecule with the aim of improving their ability to bind DNA. The new compound, MEN 10710 (II), has a four pyrrolecarboxamide backbone linked at its N-terminus and through a butanamido residue to a 4-[bis(chloroethyl)amino]phenyl moiety. We have demonstrated that the presence of the flexible trimethylene chain confers to the novel distamycin derivative a peculiar mode of interaction with DNA as compared with I or melphalan. In fact, interstrand cross-links are detected in DNA samples treated even with low concentrations of II (being 200-fold more efficient than melphalan) but not with I. Similar results were obtained with a related compound of II containing a three pyrrole ring backbone. Compound II induces a conformational change in the DNA structure as deduced from the inhibition of T4 DNA ligase activity. In alkylation experiments, unlike melphalan, both I and II induce DNA breaks at bases closely located to AT-rich tracts, however II was more potent than I in producing greater amount of covalent adducts. These data suggest that the new compound shows a different and peculiar mechanism of interaction with DNA.

Full Text

The Full Text of this article is available as a PDF (87.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Animati F., Arcamone F. M., Conte M. R., Felicetti P., Galeone A., Lombardi P., Mayol L., Paloma L. G., Rossi C. Synthesis of two distamycin analogues and their binding mode to d(CGCAAATTTGCG)2 in the 2:1 solution complexes as determined by two-dimensional 1H-NMR. J Med Chem. 1995 Mar 31;38(7):1140–1149. doi: 10.1021/jm00007a011. [DOI] [PubMed] [Google Scholar]
  2. Arcamone F. M., Animati F., Barbieri B., Configliacchi E., D'Alessio R., Geroni C., Giuliani F. C., Lazzari E., Menozzi M., Mongelli N. Synthesis, DNA-binding properties, and antitumor activity of novel distamycin derivatives. J Med Chem. 1989 Apr;32(4):774–778. doi: 10.1021/jm00124a008. [DOI] [PubMed] [Google Scholar]
  3. Broggini M., Erba E., Ponti M., Ballinari D., Geroni C., Spreafico F., D'Incalci M. Selective DNA interaction of the novel distamycin derivative FCE 24517. Cancer Res. 1991 Jan 1;51(1):199–204. [PubMed] [Google Scholar]
  4. Ciucci A., Feriotto G., Mischiati C., Gambari R., Animati F., Lombardi P., Natali P. G., Arcamone F., Giacomini P. Distamycin analogues with improved sequence-specific DNA binding activities. Biochem Pharmacol. 1994 Oct 18;48(8):1583–1591. doi: 10.1016/0006-2952(94)90203-8. [DOI] [PubMed] [Google Scholar]
  5. Feriotto G., Ciucci A., Mischiati C., Animati F., Lombardi P., Giacomini P., Arcamone F., Gambari R. Binding of Epstein-Barr virus nuclear antigen 1 to DNA: inhibition by distamycin and two novel distamycin analogues. Eur J Pharmacol. 1994 Apr 15;267(2):143–149. doi: 10.1016/0922-4106(94)90165-1. [DOI] [PubMed] [Google Scholar]
  6. Fontana M., Lestingi M., Mondello C., Braghetti A., Montecucco A., Ciarrocchi G. DNA binding properties of FCE24517, an electrophilic distamycin analogue. Anticancer Drug Des. 1992 Apr;7(2):131–141. [PubMed] [Google Scholar]
  7. Hartley J. A., Berardini M. D., Souhami R. L. 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. 1991 Feb 15;193(1):131–134. doi: 10.1016/0003-2697(91)90052-u. [DOI] [PubMed] [Google Scholar]
  8. Hartley J. A., Gibson N. W., Kohn K. W., Mattes W. B. DNA sequence selectivity of guanine-N7 alkylation by three antitumor chloroethylating agents. Cancer Res. 1986 Apr;46(4 Pt 2):1943–1947. [PubMed] [Google Scholar]
  9. Hartley J. A., Gibson N. W., Kohn K. W., Mattes W. B. DNA sequence selectivity of guanine-N7 alkylation by three antitumor chloroethylating agents. Cancer Res. 1986 Apr;46(4 Pt 2):1943–1947. [PubMed] [Google Scholar]
  10. Mattes W. B., Hartley J. A., Kohn K. W. DNA sequence selectivity of guanine-N7 alkylation by nitrogen mustards. Nucleic Acids Res. 1986 Apr 11;14(7):2971–2987. doi: 10.1093/nar/14.7.2971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Mattes W. B., Hartley J. A., Kohn K. W. DNA sequence selectivity of guanine-N7 alkylation by nitrogen mustards. Nucleic Acids Res. 1986 Apr 11;14(7):2971–2987. doi: 10.1093/nar/14.7.2971. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Mattes W. B., Hartley J. A., Kohn K. W., Matheson D. W. GC-rich regions in genomes as targets for DNA alkylation. Carcinogenesis. 1988 Nov;9(11):2065–2072. doi: 10.1093/carcin/9.11.2065. [DOI] [PubMed] [Google Scholar]
  13. Modrich P., Lehman I. R., Wang J. C. Enzymatic joining of polynucleotides. XI. Reversal of Escherichia coli deoxyribonucleic acid ligase reaction. J Biol Chem. 1972 Oct 10;247(19):6370–6372. [PubMed] [Google Scholar]
  14. Montecucco A., Ciarrocchi G. AMP-dependent DNA relaxation catalyzed by DNA ligase occurs by a nicking-closing mechanism. Nucleic Acids Res. 1988 Aug 11;16(15):7369–7381. doi: 10.1093/nar/16.15.7369. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Montecucco A., Fontana M., Focher F., Lestingi M., Spadari S., Ciarrocchi G. Specific inhibition of human DNA ligase adenylation by a distamycin derivative possessing antitumor activity. Nucleic Acids Res. 1991 Mar 11;19(5):1067–1072. doi: 10.1093/nar/19.5.1067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Montecucco A., Lestingi M., Pedrali-Noy G., Spadari S., Ciarrocchi G. Use of ATP, dATP and their alpha-thio derivatives to study DNA ligase adenylation. Biochem J. 1990 Oct 1;271(1):265–268. doi: 10.1042/bj2710265. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Montecucco A., Pedrali-Noy G., Spadari S., Ciarrocchi G. Multiple roles of DNA ligase at the replication fork. Biochim Biophys Acta. 1988 Dec 20;951(2-3):330–334. doi: 10.1016/0167-4781(88)90103-0. [DOI] [PubMed] [Google Scholar]
  18. Montecucco A., Pedrali-Noy G., Spadari S., Lestingi M., Ciarrocchi G. Effects of DNA-binding drugs on T4 DNA ligase. Biochem J. 1990 Mar 1;266(2):379–384. doi: 10.1042/bj2660379. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Montecucco A., Pedrali-Noy G., Spadari S., Zanolin E., Ciarrocchi G. DNA unwinding and inhibition of T4 DNA ligase by anthracyclines. Nucleic Acids Res. 1988 May 11;16(9):3907–3918. doi: 10.1093/nar/16.9.3907. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES