Martine Demeunynck

Abasic DNA structure, reactivity, and recognition.

Loss of a base in DNA, i.e., creation of an abasic site leaving a deoxyribose residue in the strand, is a frequent lesion that may occur spontaneously, or under the action of radiations and alkylating agents, or enzymatically as an intermediate in the repair of modified or abnormal bases. The abasic site lesion is mutagenic or lethal if not repaired. From a chemical point of view,the abasic site is an alkali-labile residue that leads to strand breakage through beta- and delta- elimination. Progress in the understanding of the chemistry and enzymology of abasic DNA largely relies upon the study of synthetic abasic duplexes. Several efficient synthetic methods have thus been developed to introduce the lesion (or a stable analogue) at defined position in the sequence. Physicochemical and spectroscopic examination of such duplexes, including calorimetry, melting temperature, high-field nmr and molecular modeling indicate that the lesion strongly destabilizes the duplex, although remaining in the canonical B-form with structural modifications strictly located at the site of the lesion. Probes have been developed to titrate the damage in DNA in vitro. Series of molecules have been devised to recognize specifically the abasic site, exhibiting a cleavage activity and mimicking the AP nucleases. Others have been prepared that bind strongly to the abasic site and show promise in potentiating the cytotoxic and antitumor activity of the clinically used nitrosourea (bis-chloroethylnitrosurea).

Interest of Acridine Derivatives in the Anticancer Chemotherapy

DNA is considered as one of the main targets for anticancer drug design. The planar structure of acridines confers to the molecules the ability to bind DNA by intercalation and therefore to interfere with metabolic processes. A large number of natural alkaloids and synthetic acridine derivatives have been tested as anticancer agents. So far, a few molecules have entered clinical trials and have been approved for chemotherapy. The mechanisms of action are not fully understood. Cytotoxicity may be related to potent enzyme inhibition. Topoisomerase and telomerase activities may be strongly affected by acridines. The affinity of acridines for DNA has also been used to design new active compounds in which a DNA modifying group is tethered to the acridine nucleus. Acridine derivatives display other pharmacological properties such as antibacterial and antimalarial activities. They are also tested for Alzheimers disease.

Nucleic acid conformation diversity: from structure to function and regulation

Nucleic acids are the structural supports of genetic material and therefore the key factors in many vital cellular processes. The double-stranded right-handed helix is a regular conformation adopted by both DNA and RNA in cells, but an increasing number of results point to the biological importance of alternative structures such as bulges, hairpins, branched junctions or quadruplexes. Progress in the chemical synthesis of oligonucleotides and in the knowledge of the factors that favour a particular conformation has opened new fields of research in molecular recognition and drug design.

Synthesis and characterisation of a new DNA-binding bifunctional ruthenium(II) complex

A new DNA-binding molecule, Ru(tap)2POQ2+, in which a polypyridylruthenium(II) complex is linked to an aminochloroquinoline by a flexible chain, has been prepared and characterised (tap = 1,4,5,8-tetraazaphenanthrene and POQ corresponds to a 1,10-phenanthroline linked to an aminochloroquinoline by an aliphatic chain). This complex is regarded as bifunctional because it contains two moieties of different binding modes and photoreactivities vs. DNA. The 1H NMR data of this compound indicate the presence of an equilibrium between two molecular species. The spectroscopic properties of Ru(tap)2POQ2+ in absorption and luminescence are examined and compared with those of the corresponding ruthenium(II) complex which does not contain the aminochloroquinoline moiety: Ru(tap)2phen2+. Luminescence relative quantum yields and lifetimes show that the MLCT excited-state behaviour is influenced by the presence of the linked quinoline. An intramolecular photoinduced electron transfer in one of the two species in equilibrium, is considered to be responsible for a quenching of the ruthenium(II) complex iuminescence. Preliminary results on the binding characteristics of Ru(tap)2POQ2+ to DNA and [poly(d[A-T])]2 from luminescence and thermal denaturation studies are reported. The intramolecular quenching of luminescence in Ru(tap)2POQ2+ is inhibited when it interacts with nucleic acids. Consequently, the resulting emission is more substantially enhanced in the presence of the polynucleotide relative to the luminescence increase observed with the reference complex, Ru(tap)2phen2+.

Synthesis of tröger's base analogs derived from 3-aminoacridine and 10-aminobenzo[b][1,7]phenanthroline

Abstract The heterocyclic aromatic amines 10-aminobenzo[b][1,7]phenanthroline 1 and 3-aminoacridine 2 react regioselectively with formaldehyde in acidic medium to yield the Trogers base analogs 7 and 8.

Tetrapyrido[3,2-a:2′,3′-c:3″,2″-h:2‴,3‴-j]acridine (tpac): a new extended polycyclic bis-phenanthroline ligand

A new heptacyclic planar molecule has been synthesized in a very efficient one-pot reaction from 5-aminophenanthroline. Ru(II) mono- and dinuclear complexes based on this new bridging ligand, Tpac, have been prepared.

Survey of recent literature related to the biologically active 4(3H)-quinazolinones containing fused heterocycles.

The present review focuses on the synthesis and biological evaluation of polycyclic 4(3H)-quinazolinones containing fused aromatic or heteroaromatic rings. The first part of the review is related to compounds with ring fused to the pyrimidine part of the quinazoline core. Most of the quinazolinone alkaloids belong to this class of molecules. The second part presents molecules bearing extra ring(s) fused to the benzo moiety of the quinazolinone skeleton. Their structural diversity opens new fields in the search of active molecules.

A phenanthroline analogue of Tröger's base as bridging ligand in the synthesis of a bimetallic ruthenium (II) complex

Complexation of a Phenanthroline analogue of Trogers Base 2 to Ru(Bpy)22+ units results in the formation of a dinuclear complex 3. The spectroscopic data in absorption and emission indicate that the resulting dinuclear compound 3 behaves as two independent monometallic Ru(II) complexes.

SYNTHESIS OF POLYFUNCTIONALIZED TROGER'S BASE ANALOGS DERIVED FROM ETHACRIDINE (6,9-DIAMINO-2-ETHOXYACRIDINE)

Abstract In the search for chemical probes of DNA conformations, we report an efficient synthesis of new Trogers Base analogs derived from polyfunctionalized aminoacridines treated with a stoechiometric amount of formaldehyde in trifluoroacetic acid. For the more sensitive aminoacridines, the Trogers Bases were obtained by nucleophilic substitution of the chloro group of the “pre-formed” corresponding Trogers Base.

Synthesis and study of an acridine substituted Tröger’s base: preferential binding of the (–)-isomer to B-DNA

The acridine substituted Troger’s base 4 was prepared, resolved and the (–)-(7R,17R) enantiomer was shown to bind preferentially to calf-thymus B-DNA.