Ivo Piantanida

Novel Amidino-Substituted Thienyl-and Furylvinylbenzimidazole : Derivatives and Their Photochemical Conversion into Corresponding Diazacyclopenta[c]fluorenes. Synthesis, Interactions with DNA and RNA, and Antitumor Evaluation. 4

Synthesis of novel nonfused amidino-substituted thienyl- and furylvinylbenzimidazole: derivatives and their photochemical cyclization into corresponding diazacyclopenta[ c]fluorenes is described. All studied compounds showed prominent growth inhibitory effect. The fused compounds showed stronger activity than nonfused ones, whereby imidazolyl-substituted compound 11 proved to be the most active one. Besides, it induced strong G2/M arrest of the cell cycle followed by drastic apoptosis, which is in accordance with the DNA intercalative binding mode determined by the spectroscopic studies. Nonfused derivatives induced strong S phase arrest of the cell cycle followed by apoptosis that together with DNA minor groove binding mode pointed to topoisomerase I inhibition. In addition, all nonfused compounds revealed pronounced selectivity toward tumor cells in comparison with nontumor cells. On the basis of the presented results, both nonfused and fused thiophene-containing imidazolyl derivatives should be considered as promising lead compounds for further investigation.

Phenanthridinium cyclobisintercalands. Fluorescence sensing of AMP and selective binding to single-stranded nucleic acids

Abstract Macrocyclic ligands 1 and 2 containing two positively charged phenanthridinium units and aminobisacetylenic bridges, exhibit significantly higher affinity toward single-stranded rather than double-stranded polynucleotides. The ligands bis-intercalate into the former and show non-intercalative interactions with the latter type of nucleic acids. Both ligands differentiate AMP from the GMP or UMP by significant fluorescence emission increase upon complexation of the first nucleotide in water (logxa0 K s of 1:1 and 1:2 complexes 5.8 and 1.4, respectively), while only a slight emission change is observed in titrations with GMP and UMP.

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 [3H]-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.

Synthesis, antitumor evaluation and DNA binding studies of novel amidino-benzimidazolyl substituted derivatives of furyl-phenyl- and thienyl-phenyl-acrylates, naphthofurans and naphthothiophenes

A series of amidino-substituted benzimidazoles, related to furyl-phenyl- and thienyl-phenyl-acrylates, naphthofurans and naphthothiophenes were prepared, their antitumor evaluation and interactions with ct-DNA have been investigated. All tested compounds show differential and strong antitumor activity without apparent difference depending on their structures. Interestingly, the MCF-7 tumor cell line is highly sensitive to all compounds. Compounds 6-9 showed noticeable selectivity in regard to normal fibroblasts (WI 38). Compounds 4-9 interact with ct-DNA by more binding modes, whose mutual distribution is dependent on the compound/DNA ratio. The acyclic4-6 and cyclic compound 7 interact mostly within the minor groove of DNA, although partial intercalation of 6 and 7 cannot be excluded. The cyclic compounds 8 and 9 intercalate between DNA base pairs at high excess of DNA over compounds.

Novel imidazo[4,5-b]pyridine and triaza-benzo[c]fluorene derivatives: Synthesis, antiproliferative activity and DNA binding studies

In the present paper, we have described the synthesis and biological activity of the novel derivatives of imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes (7-21, 24-26, 28-29). A preponderance of these compounds exerted strong cytostatic effects on the panel of seven human tumour cell lines in a dose-dependent manner. In particular, imidazo[4,5-b]pyridines and triaza-benzo[c]fluorenes including 2-imidazolinyl derivatives showed the most potent antitumour activity. Similarly, triaza-benzo[c]fluorenes 18 and 20 induced strong growth inhibition of tested tumour cell lines, and showed low cytotoxicity in normal human fibroblasts. DNA interaction studies of these compounds demonstrated that N-methylated 16 and 2-imidazolinyl 28 triaza-benzo[c]fluorenes bind to DNA in an intercalative mode.

Crystal and molecular structures of diazapyrenes and a study of π\cdotsπ 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, P21/c, a = 4.0246u2005(5), b = 15.5147u2005(5), c = 9.1453u2005(9)u2005A, β = 101.23u2005(1)°, V = 560.1u2005(1)u2005A3, Z = 2, R = 0.043; (2) monoclinic, C2/m, a = 12.4968u2005(3), b = 11.4751u2005(4), c = 3.9615u2005(5)u2005A, β = 96.80u2005(1)°, V = 564.09u2005(5)u2005A3, 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. πcdotsπ 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 πcdotsπ 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 β and a few cases of γ 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 β-type structures and the crystal structure of graphite.

Complex formation of quercetin with lanthanum enhances binding to plant viral satellite double stranded RNA

Due to the broad spectrum of biological activities of flavonoids, their target molecules in the cell are intensively studied. We examined the interactions of the flavonoid quercetin (Q) and its lanthanum complex (QLa(3+)) with very recently isolated plant viral satellite (sat) dsRNA. Comparison of the cumulative binding affinity and the estimated intercalative binding constant pointed towards an additional binding mode of quercetin to exclusively viral dsRNA, which is not recorded for synthetic dsRNAs. The QLa(3+) showed significantly higher affinity toward viral dsRNA than Q and La(3+) alone, most likely as the consequence of quercetin intercalation accompanied by additional electrostatic interaction of La(3+) with the negatively charged viral RNA backbone.

Pentamidine analogs as inhibitors of [3H]MK-801 and [3H]ifenprodil binding to rat brain NMDA receptors

The anti-protozoal drug pentamidine is active against opportunistic Pneumocystis pneumonia, but in addition has several other biological targets, including the NMDA receptor (NR). Here we describe the inhibitory potencies of 76 pentamidine analogs at 2 binding sites of the NR, the channel binding site labeled with [(3)H]MK-801 and the [(3)H]ifenprodil binding site. Most analogs acted weaker at the ifenprodil than at the channel site. The spermine-sensitivity of NR inhibition by the majority of the compounds was reminiscent of other long-chain dicationic NR blockers. The potency of the parent compound as NR blocker was increased by modifying the heteroatoms in the bridge connecting the 2 benzamidine moieties and also by integrating the bridge into a seven-membered ring. Docking of the 45 most spermine-sensitive bisbenzamidines to a recently described acidic interface between the N-terminal domains of GluN1 and GluN2B mediating polyamine stimulation of the NR revealed the domain contributed by GluN1 as the most relevant target.