Recognition of single stranded and double stranded DNA/RNA sequences in aqueous medium by small bis-aromatic derivatives.

The aim of this review is to summarize the most comprehensive results in the field of bis-aromatic compounds targeting DNA and RNA, whereby both aromatic units of small molecule bind to the polynucleotide by the aromatic stacking interactions. The most recent results about structure - DNA/RNA binding affinity, selectivity and biological implications are discussed for bis-intercalators, sterically restricted macrocyclic and threading bis-aromatics and intercalator - nucleobase conjugates.

Synthesis of phenanthridinium-bis-nucleobase conjugates, interactions with poly U, nucleotides and in vitro antitumour activity of mono- and bis-nucleobase conjugates.

Novel bis-nucleobase-phenanthridinium conjugates were synthesised and their aqueous solutions spectroscopically characterised. Bis-adenine conjugate revealed in aqueous solutions significantly more pronounced intramolecular aromatic stacking interactions than bis-uracil analogue. In contrast with previously reported poly A recognition by bis-uracil conjugate, recognition of complementary nucleotides and poly U was not observed due to the strong interference of bulk water with hydrogen bonding between nucleobases. The screening of anticancer activity on six human cell lines revealed that tethering of a nucleobase to phenanthridinium moiety diminished antiproliferative potential of phenanthridinium. However, among mono-nucleobase conjugates adenine derivative was found to be the most selective one (MiaPaCa-2, Hep-2).

In vitro cytotoxicity of three 4,9-diazapyrenium hydrogensulfate derivatives on different human tumor cell lines.

DNA intercalating agents interfere with DNA's role as a template in replication and transcription by inserting an intercalator molecule between adjacent base pairs. We synthesized three potential novel intercalators, 4,9-diazapyrenium hydrogensulfate derivatives: 5, 10-diphenyl-4,9-dimethyl-4,9-diazapyrenium hydrogensulfate (FDAP), 4, 9-dimethyl-4,9-diazapyrenium hydrogensulfate (GDAP) and 2,4,7, 9-tetramethyl-4,9-diazapyrenium hydrogensulfate (MDAP) and tested their biological effects in vitro on four human tumor cell lines (SKBr3: breast carcinoma, HeLa: cervical carcinoma, CaCo2: colon carcinoma and SW620: poorly differentiated cells from lymph node metastasis of colon carcinoma). Cytotoxic effects on cell growth and viability were determined using tetrazolium dye (MTT) assay. DNA synthesis and proliferation of treated cells were studied by the [(3)H]-thymidine incorporation test. DNA fragmentation was analyzed by agarose gel electrophoresis. The growth inhibitory effect was cell-specific and dose-dependent. The most pronounced antiproliferative effect was observed on SKBr3 cells for FDAP (10(-5) M) 91.8%, for MDAP (10(-5) M) 85.3% and on SW620 cells for GDAP (10(-5) M) 65.3%. The DNA ladder fragmentation of treated HeLa and SKBr3 cells, as a hallmark of apoptosis, was observed. Based on specific DNA fragmentation, morphological changes (reduced cell volume, round cell shape, condensed chromatin) and growth inhibition of treated human tumor cells we conclude that tested substances induced apoptotic cell death.

Crystal and molecular structures of diazapyrenes and a study of pi\cdotspi interactions.

Two diazapyrenes, 5,10-dimethyl-4,9-diazapyrene (1) and novel 2,7-dimethyl-4,9-diazapyrene (2) have been synthesized. Their crystal structures are reported here and are the first representatives of diazapyrenes. Crystal data: (1) monoclinic, P2(1)/c, a = 4.0246 (5), b = 15.5147 (5), c = 9.1453 (9) Å, beta = 101.23 (1) degrees, V = 560.1 (1) Å(3), Z = 2, R = 0.043; (2) monoclinic, C2/m, a = 12.4968 (3), b = 11.4751 (4), c = 3.9615 (5) Å, beta = 96.80 (1) degrees, V = 564.09 (5) Å(3), Z = 2, R = 0.0405. The experimental bond lengths are compared with those calculated by molecular mechanics (MM3), semi-empirical methods (MOPAC6.0-PM3, AM1, MNDO) and values predicted by valence-bond and variable-electronegativity self-consistent field (VESCF) methods. pi.pi interactions in (1), (2) and seventeen other pyrene and pyrene-like molecules selected from the Cambridge Structural Database [Allen & Kennard (1993). Chem. Des. Autom. News, 8, 131-137] have been studied. The following quantitative parameters of pi.pi interactions have been calculated: the shortest crystallographic axis, the offset parameter, the interplanar angle, the interactive volume and the overlapping surfaces. They are used for the classification of crystal-packing motifs; a high predominance of beta and a few cases of gamma and sandwich-herringbone types are observed. In addition, electronegativity, the sum of partial atomic charges of the ring non-H atoms and the number of aromatic skeleton electrons are used as parameters for classification. MOPAC-PM3 was used to calculate the partial atomic charges in (1), (2) and pyrene analogues. Correlations between geometrical and electronic structure parameters reveal an analogy between the beta-type structures and the crystal structure of graphite.

4,9-diazapyrenium dications induce apoptosis in human tumor cells.

We investigated the antiproliferative effects of two planar 4,9-diazapyrenium hydrogenasulphates against human malignant MiaPaCa 2 (pancreatic carcinoma), Hep 2 (laryngeal carcinoma) and human normal fibroblasts (WI 38) cell lines. The tested compounds were very potent in inhibiting the growth of the treated cell lines. Treatment with molar concentrations of the substances (10(-4)-10(-7) M) caused growth inhibition by more than 50%. The morphological changes of treated cells were also observed. Cells became smaller, with condensed chromatin and fragmented nuclei, the characteristics of dying cells. The identification of DNA-fragmentation and the appearance of chromatin aggregation leads us to assume the tested substances induced apoptosis of the investigated tumor cell lines.