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).

Synthesis and antitumor activity of N-sulfonyl derivatives of nucleobases and sulfonamido nucleoside derivatives.

The introduction of sulfonamido group on the C-2 position of pyrimidine nucleosides was achieved by ring opening of 2,2'- and 2,3'-anhydronucleosides. N-sulfonyl derivatives of nucleobases and sulfonamido derivatives of nucleosides were assayed for in vitro antitumor activity.

Benzdiamidine.

The molecule of benzene-1,4-dicarboxamidine or benzdiamidine, C(8)H(10)N(4), reveals C(i) symmetry. Hydrogen bonds utilize the amino groups as double donors, whereas the imino groups act as double acceptors. The network formed is similar to that observed in the crystal packing of terephthalamide.

Bis(amino acid) oxalyl amides as ambidextrous gelators of water and organic solvents: supramolecular gels with temperature dependent assembly/dissolution equilibrium.

Bis(LeuOH) (1a), bis-(ValOH) (2a) and bis(PhgOH) (5a) (Phg denotes (R)-phenylglycine) oxalyl amides are efficient low molecular weight organic gelators of various organic solvents and their mixtures as well as water, water/DMSO, and water/DMF mixtures. The organisational motifs in aqueous gels are dominated primarily by lipophilic interactions while those in organic solvents are formed by intermolecular hydrogen bonding. Most of the gels are thermoreversible and stable for many months. However, 2a forms unstable gels with organic solvents which upon ageing transform into variety of crystalline shapes. For some 1a/alcohol gels, a linear correlation between alcohol dielectric constants (epsilon) and gel melting temperatures (Tg) was found. The 1H NMR and FTIR spectroscopic investigations of selected gels reveal the existence of temperature dependent network assembly/dissolution equilibrium. In the 1H NMR spectra of gels only the molecules dissolved in entrapped solvent could be observed. By using an internal standard, the concentration of dissolved gelator molecules could be determined. In FTIR spectra, the bands corresponding to network assembled and dissolved gelator molecules are simultaneously present. This enabled determination of the Kgel values by using both methods. From the plots of InKgel versus 1/T, the deltaHgel values of selected gels have been determined (-deltaHgel in 10-36 kJ mol(-1) range) and found to be strongly solvent dependent. The deltaHgel values determined by 1H NMR and FTIR spectroscopy are in excellent agreement. Crystal structures of 2a and rac-5a show the presence of organisational motifs and intermolecular interactions in agreement with those in gel fibres elucidated by spectroscopic methods.

Intermolecular contacts in the crystal packing of 2,2'-(N,N'-oxalyldiimino)bis(3-phenylpropanamide) dimethyl sulfoxide solvate.

In the title compound, C20H22N4O4*C2H6OS, two distinct hydrogen-bond systems connect oxalamide groups in one pattern and primary amide groups in the other to form a two-dimensional network perpendicular to the c axis. These hydrophilic layers are joined to the three-dimensional structure through C--H...pi interactions. The hydrogen-bonded waved layers shape holes which are occupied by disordered dimethyl sulfoxide solvent molecules.

meso-N,N'-oxalyldivaline.

The title compound, 2,2'-(oxalyldiimino)bis(3-methylbutanoic acid), C12H20N2O6, possesses a centre of symmetry. In the crystal, molecules are connected by hydrogen bonds between oxamide and carboxyl groups, similar to the pattern of the monoclinic forms of HO-Gly-CO-CO-Gly-OH and HO-Aib-CO-CO-Aib-OH (Gly is glycine and Aib is 2-aminoisobutyric acid). The characteristic torsion angles in the title compound are close to those in peptide alpha-helices.

Calix

Chiral calix[4]arene derivatives with four O-(N-acetyl-PhgOMe), (1), (Phg denotes R-phenylglycine), or O-(N-acetyl-LeuOMe) (2) strands have been synthesised. Both compounds exist in chloroform in stable cone conformations with a noncovalently organised cavity at the lower rim that is formed by circular interstrand amidic hydrogen bonds. Such organisation affects both the selectivity and extraction/transport properties of 1 and 2 toward metal cations. Calix[4]arene derivatives with one OCH2COPhgOMe strand (3), two OCH2COPhgOMe strands (5) and with 1,3-OMe-2,4-(O-CH2COPhgOMe) substituents (4) at the lower rim have also been prepared. For 3, a conformation stabilised by a circular hydrogen-bond arrangement is found in chloroform, while 4 exists as a time-averaged C2 conformation with two intramolecular NH ...OCH3 hydrogen bonds. Compound 5 has a unique hydrogen-bonding motif in solution and in the solid state with two three-centred NH-.. O and two OH...O hydrogen bonds at the lower rim. This motif keeps 5 in the flattened cone conformation in chloroform. The X-ray structure analysis of 1 revealed a molecular structure with C2 symmetry; this structure is organised in infinite chains by intra- and intermolecular H bonds. The solid-state and solution structures of the [1-Na]ClO4 complex are identical, C4 symmetric cone conformations.

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.