Minor structural differences of monomethine cyanine derivatives yield strong variation in their interactions with DNA, RNA as well as on their in vitro antiproliferative activity

Bioorg Med Chem. 2009 Jul 1;17(13):4747-55. doi: 10.1016/j.bmc.2009.04.070. Epub 2009 May 6.

Abstract

Comparison of binding properties of a series of monomethine cyanine derivatives to ds-DNA and ds-RNA revealed significant impact of the properties of substituent attached to the longer axis of aromatic core. Namely, it seems that only compounds 7, 8 characterised by length of longer axis not exceeding the length of longer axis of basepairs could intercalate into ds-DNA and ds-RNA, while the increased substituent length and additional possibility of hydrogen bonds formation directed binding of 1-6 into ds-DNA minor groove. Consequent ds-RNA over ds-DNA selectivity of 7 and 8 is the most appealing and rather rare property among small molecules. The interactions of 1-8 with ss-RNA were strongly dependent on both, structure of compound and base composition of RNA. The cytotoxicity screening of compounds 1-8 by MTT test revealed considerable antiproliferative activity against solid tumours and especially toward haematological malignancies (IC(50)=0.001-6.6 microM), whereby normal human aortic endothelial cells (HAEC) were significantly less affected (IC(50)=1-200 microM). The cells of chronic myeloid leukaemia in blast crisis (K562) were especially sensitive to all tested compounds (IC(50)=0.001-0.6 microM), while normal lymphocytes were more resistant (IC(50)=0.01-1 microM). Results of uptake and intracellular distribution of compounds 1 and 2 in the living cells showed that they do not bind primarily to nuclear DNA but their fluorescence is scattered through the whole cells. A detailed mechanism of antitumor activity of tested molecules remains to be investigated.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics
  • Antineoplastic Agents / pharmacology*
  • Benzothiazoles / chemistry*
  • Benzothiazoles / pharmacokinetics
  • Benzothiazoles / pharmacology*
  • Binding Sites
  • Cattle
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • DNA / chemistry
  • DNA / metabolism*
  • Humans
  • Models, Molecular
  • Neoplasms / drug therapy
  • Nucleic Acid Denaturation / drug effects
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • RNA / chemistry
  • RNA / metabolism*
  • RNA, Double-Stranded / chemistry
  • RNA, Double-Stranded / metabolism
  • Spectrometry, Fluorescence
  • Structure-Activity Relationship
  • Temperature
  • Titrimetry

Substances

  • Antineoplastic Agents
  • Benzothiazoles
  • Pyrimidines
  • RNA, Double-Stranded
  • RNA
  • DNA