Synthesis and Structural Characterization of Pyridine-2,6-dicarboxamide and Furan-2,5-dicarboxamide Derivatives.

Derivatives based on pyridine-2-6- and furan-2,5-dicarboxamide scaffolds reveal numerous chemical properties and biological activities. This fact makes them an exciting research topic in supramolecular and coordination chemistry and in discovering new pharmacologically-active compounds. This work aimed to obtain a series of symmetrical pyridine-2-6- and furan-2,5-dicarboxamides through a condensation reaction of the appropriate acyl chlorides and aromatic amides. Successful syntheses were confirmed with NMR spectroscopy. We solved their crystal structures for seven compounds; two pyridine and five furan derivatives. Based on our crystallographic studies, we were able to indicate supramolecular features of the crystals under investigation. Additionally, Hirshfeld surface analysis allowed us to calculate a distribution of intermolecular contacts in the dicarboxamide crystals.

Carbocyclic Analogues of Distamycin and Netropsin.

The DNA as the depository of genetic information is a natural target for chemotherapy. A lot of anticancer and antimicrobial agents derive their biological activity from their selective interaction with DNA in the minor groove and from their ability to interfere with biological processes such as enzyme catalysis, replication and transcription. The discovery of the details of minor groove binding drugs, such as netropsin and distamycin A, oligoamides built of 4-amino-1-methylpyrrole-2-carboxylic acid residues, allowed to develop various DNA sequence-reading molecules, named lexitropsins, capable of interacting with DNA precisely, strongly and with a high specificity, and at the same time exhibiting significant cytotoxic potential. Among such compounds, lexitropsins built of carbocyclic sixmembered aromatic rings occupy a quite prominent place in drug research. This work is an attempt to present current findings in the study of carbocyclic lexitropins, their structures, syntheses and biological investigations such as DNA-binding and antiproliferative activity.

Design and synthesis of potent hydroxamate inhibitors with increased selectivity within the gelatinase family.

MMP-2 is a validated target for the development of anticancer agents. Herein we describe the synthesis of a new series of potent phenylalanine derived hydroxamates, with increased MMP-2/MMP-9 selectivity compared to analogous hydroxamates described previously. Docking and molecular dynamics experiments have been used to account for this selectivity, and to clarify the role of the triazole ring in the binding process.

Amino and chlorambucil analogues of pentamidine--synthesis and biological examinations.

The amino analogues of pentamidine with a polymethylene (n = 3 - 6) chain and their chlorambucil derivatives were synthesized. The obtained compounds revealed cytotoxic effect on MCF-7 human breast cancer cell line (IC50 = 22 - 95 +/- 2 pM), mainly by the induction of apoptosis. The topoisomerase I/II inhibition assay and the ethidium displacement assay with the use of pBR322 plasmid DNA were used to the study of mechanism by which the obtained compounds could act. All the compounds are able to bind with DNA and interfere in vitro with the activity of topoisomerase (I and II). The determination of association constants with the use of calf thymus DNA, T4 coliphage DNA, poly(dA-dT)2 and poly(dG-dC)2 showed that the tested compounds bind within minor groove of B-DNA, but not selectively. The alkylating activity of chlorambucil derivatives determined in vitro using a Preussmann test was similar to the activity of chlorambucil. The influence of all the compounds on the amidolytic activity of plasmin and trypsin was also examined. The plasmin activity was inhibited by pentamidine, chlorambucil and aromatic bis-amines (IC50 = 0.1 - 8 mM), whereas the trypsin activity was influenced only by pentamidine.

Effects of netropsin and pentamidine amino analogues on the amidolytic activity of plasmin, trypsin and urokinase.

Inhibitory effects of nine carbocyclic DNA minor groove binders on amidolytic activities of plasmin, trypsin and urokinase were examined. Some of the studied compounds affected plasmin or trypsin activity, but not urokinase activity. One of the pentamidine analogues (5) and two bis-netropsin like compounds (6, 8) were potent inhibitors of plasmin (IC50 equals 90 and 100 microM), whereas an analogue of netropsin (2) was trypsin inhibitor (IC50 = 100 microM).

Carbocyclic analogues of lexitropsin--DNA affinity and endonuclease inhibition.

A DNA-binding affinity and the effect on restriction enzymes activity of seven carbocyclic mono- and bis-lexitropsins and two analogues of pentamidine with unsubstituted N-terminal amine group were investigated. DNA association constants (Kapp) show that DNA affinity of mono-compounds is much weaker than netropsin and distamycin. Bis-analogues of netropsin bind DNA more strongly than mono-ligands, but without sequence-selectivity. Only pentamidine derivatives reveal preference to AT-rich sequence. The studied compounds can inhibit catalytical action of endonucleases recognizing sequence of four AT base pairs following one another.

Aromatic benzotriazole amides--synthesis and biological evaluation.

Four derivatives of benzotriazole-5-carboxylic acid were synthesized as potential UV-light dependent DNA cleaving agent. The effect of these compounds on phiX174 RF1 phage DNA and pBR322 plasmid DNA was investigated with and without UV exposure. It has been found that the two compounds exert the influence on topological forms of DNA.

Aromatic analogues of DNA minor groove binders--synthesis and biological evaluation.

Nine carbocyclic analogues of mono- and bis-lexitropsins and two analogues of pentamidine with unsubstituted N-terminal amine group were synthesized. We have investigated the cytotoxic activity of new aromatic analogues of DNA binding ligands in MCF-7 breast cancer cells and assessed their ability to act as inhibitors of topoisomerase I and II. These studies indicate that aromatic analogues of bis-netropsin contain two identical units tethered by alkyloxyl chains are a potent catalytic inhibitor of both topoisomerases and exhibit moderate cytotoxicity in MCF-7 breast cancer cells.

New carbocyclic analogues of netropsin: synthesis and inhibition of topoisomerases.

A series of carbocyclic analogues of netropsin were synthesized and evaluated for their capacity to inhibit human topoisomerases I and II in vitro. The compounds are oligopeptides containing 1,4-di- and 1,2,5-trisubstituted benzene rings and unsubstituted N-terminal NH2 groups. Compounds 4-7 consist of two netropsin-like units linked by aliphatic (tetra- and hexamethylene) chains. In the topoisomerase I and II assay, the relaxation of pBR322 plasmid was inhibited by compounds 4-7 at 100 microM concentration.