Philippe Belmont

ACRIDINE AND ACRIDONE DERIVATIVES, ANTICANCER PROPERTIES AND SYNTHETIC METHODS: WHERE ARE WE NOW?

Acridine derivatives are interesting chemotherapeutic agents that were first used as antibacterial and antiparasite agents. In this review we wish to concentrate our attention on the anticancer properties of acridines used in clinics since the 1970s. Based on recent results, an outlook on antitumour acridine chemotherapy will be proposed. The biological activity of acridines is mainly attributed to the planarity of these aromatic structures, which can intercalate within the double-stranded DNA structure, thus interfering with the cellular machinery. Recent understanding of the mode of action of acridines leads to continuous and exciting research in this heterocyclic family. Indeed, biological targets such as topoisomerases I and II, telomerase/telomere and protein kinases emerge and allow the design of novel acridine-based patterns. This review further pinpoints the latest progress in the development of anticancer agents based on naturally occurring and synthetic acridines (e.g. acridones, pyridoacridines); for this matter in vitro/in vivo studies and clinical trial results will be discussed. The DNA-affinic property of acridine is also useful to vectorise drugs into cell nuclei and some applications in hypoxia-selective treatment, platinum or N-mustard derived conjugates will be reported. Some other properties including inhibition of multidrug resistance or potential impact on Alzheimer disease will be treated. It is noteworthy that the position and the nature of the substituent on the heterocyclic core are determinants for the biological property and selectivity observed. So, we wish also to disclose a summary of recent synthetic methodologies developed for acridine synthesis.

Cyclin-Dependent Kinase Inhibitors as Marketed Anticancer Drugs: Where Are We Now? A Short Survey

In the early 2000s, the anticancer drug imatinib (Glivec®) appeared on the market, exhibiting a new mode of action by selective kinase inhibition. Consequently, kinases became a validated therapeutic target, paving the way for further developments. Although these kinases have been thoroughly studied, none of the compounds commercialized since then target cyclin-dependent kinases (CDKs). Following a recent and detailed review on the subject by Galons et al., we concentrate our attention on an updated list of compounds under clinical evaluation (phase I/II/III) and discuss their mode of action as ATP-competitive inhibitors. CDK inhibition profiles and clinical development stages are reported for the 14 compounds under clinical evaluation. Also, tentative progress for forthcoming potential ATP non-competitive inhibitors and allosteric inhibitors are briefly described, along with their limitations.

Rapid Access to Amino-Substituted Quinoline, (Di)Benzofuran, and Carbazole Heterocycles through an Aminobenzannulation Reaction

The use of a powerful aminobenzannulation reaction has been applied for the synthesis of amino-substituted quinolines, dibenzofurans, and carbazoles. The precursors are heterocycles bearing a methyl ketone group ortho to an internal alkyne. They are commercially available or can be obtained in three to four classical and efficient reactions: Vilsmeier-Haack, Sonogashira (diversity point), Grignard, and Leys oxidation. Upon aminobenzannulation reaction-classical conditions being pyrrolidine neat or in a solvent and 4 A MS-an interesting range of disubstituted quinolines, dibenzofurans, and carbazoles are obtained along with enamine formation in some cases. The reaction is useful since meta-substituted heterocycles are produced and also differs from classical heterocyclic methods which go through closure at the heteroatom-containing ring instead of benzene ring formation.

Silver-Catalyzed Domino Hydroarylation/Cycloisomerization Reactions of ortho-Alkynylbenzaldehydes: An Entry to Functionalized Isochromene Derivatives

A Ag-catalyzed versatile and efficient access to 1H,1-arylisochromenes is reported. Starting from ortho-alkynylbenzaldehydes bearing various substitution patterns on the benzaldehyde and alkynyl units, the use of silver triflate (10 mol %) allowed a domino hydroarylation/cycloisomerization reaction process, leading to aryl-functionalized 1H-isochromene (>10 compounds, 80-98% yields). Notably, the reaction conditions were also compatible with benzaldehydes bearing an aliphatic-substituted alkynyl moiety with modest to good yields (34-88%, 10 compounds).

Palladium-Catalyzed Regioselective Alkynylation of Pyrroles and Azoles under Mild Conditions: Application to the Synthesis of a Dopamine D-4 Receptor Agonist

A mild and general method for the direct alkynylation of azoles such as pyrrole, indole, and 7-azaindole is described here. Using a simple catalytic system such as Pd(OAc)2 (2.5 mol %), P(tBu)2Me·HBF4 (5 mol %), and NaOAc (2 equiv) allowed the regioselective introduction of various alkynyl residues at the C-2 position of pyrroles. Interestingly, C-2 alkynylation was also observed on C-3-substituted indoles, whereas classical C-3 alkynylation was obtained on selected unsubstituted indoles and 7-azaindole. Our methodology has been illustrated by the efficient synthesis of a potential schizophrenia drug (dopamine D-4 inhibitor).

Synthesis of an imidazo[1,2-e]purine-acridine heterodimer for targeting abasic sites in DNA

Cyclization of 8-bromo-9-alkylaminoethyl-adenine quantitatively affords a substituted imidazo[1,2-e]purine. The corresponding heterodimer, imidazo[1,2-e]purine-acridine, was prepared and its interaction with abasic site containing oligonucleotides was studied.