Synthesis of small molecules targeting multiple DNA structures using click chemistry

The ability of small molecules to target DNA forms the basis of many clinically used antitumour agents. This study examines the effects of novel 9-aminoacridine carboxamides, synthesised by click chemistry based upon the reactions of either 9-(2-azidoethyl)amino or 9-propargylaminoacridine compounds, on various types of DNA tertiary structures. This gave either monomeric or dimeric compounds, the dimeric derivatives being the first unsymmetrical acridine dimers to be described. The compounds were assayed for duplex DNA, quadruplex DNA and four-way junction DNA binding. Their antiproliferative activity in the Human promyelocytic leukaemia cell line, HL60, was also assessed. Although for some of the compounds, notably the acridine 4-carboxamides, activity correlated with DNA binding affinity, for others it did not, with the rigidly linked dimers in particular showing a complicated relationship between 3- and 4-carboxamide structure and biological activity. The monomeric 3-carboxamides were more effective at stabilising G-quadruplex structures and also gave more hits in the four-way junction stabilisation assay. There is clear evidence from the binding of the 3-carboxamides that these compounds destabilise the open X form of the junction at lower concentrations and stabilise the X-stacked at higher concentrations. This might have implications for the biological activity of these compounds against proteins that bind to the Holliday junction (HJ).     

4,9-Diaminoacridines and 4-Aminoacridines as Dual-Stage Antiplasmodial Hits

Multi-stage drugs have been prioritized in antimalarial drug discovery, as targeting more than one process in the Plasmodium life cycle is likely to increase efficiency, while decreasing the chances of emergence of resistance by the parasite. Herein, we disclose two novel acridine-based families of compounds that combine the structural features of primaquine and chloroquine. Compounds prepared and studied thus far retained the in vitro activity displayed by the parent drugs against the erythrocytic stages of chloroquine-sensitive and -resistant Plasmodium falciparum strains, and against the hepatic stages of Plasmodium berghei, hence acting as dual-stage antiplasmodial hits.     

Two‐Face,Two‐Turn α‐Helix Mimetics Based on a Cross‐Acridine Scaffold: Analogues of the Bim BH3 Domain

The design of a cross‐acridine scaffold mimicking the i, i+3, i+5, and i+7 residues distributed over a two‐face, two‐turn α‐helix is described. Docking studies and 2D ¹H,¹⁵N HSQC NMR spectroscopy provide compelling evidence that compound 3 d accurately reproduces the arrangement of four hotspots in the Bim BH3 peptide to permit binding to the Mcl‐1 and Bcl‐2 proteins (K_i 0.079 and 0.056 μM , respectively). Furthermore, the hotspot mutation could also be mimicked by individual or multiple deletions of side chains on the scaffold.     

Efficient and Tunable Thermally Activated Delayed Fluorescence Emitters Having Orientation‐Adjustable CN‐Substituted Pyridine and Pyrimidine Acceptor Units

A series of twisted D–π–A type emitters based on the acridine donor unit and CN‐substituted pyridine, pyrimidine, and benzene acceptor units are studied. They not only allow one to systematically probe the influence of different acceptor strengths, but also permit one to intriguingly probe the influence of tunable conformations (twist angles) within the acceptor moieties through controlling the orientation of asymmetric heteroaromatic ring relative to the donor component. Intramolecular charge‐transfer transitions are observed in all these compounds and emission wavelengths are widely tunable from deep blue to yellow not only by the general acceptor strength due to the characters of heteroarene and CN‐substitution pattern but also by the subtle control of in‐acceptor conformation (twist angles). Small triplet‐to‐singlet energy gaps (ΔE_ST) and significant thermally activated delayed fluorescence (TADF) characteristics are obtained in a series of D–π–A compounds with sufficient acceptor strengths and tunable in‐acceptor conformation, yielding a series of efficient blue‐green to yellow TADF emitters with promisingly high photoluminescence quantum yields of 90%–100%. Highly efficient blue‐green to yellow TADF organic light‐emitting diodes (OLEDs) having external quantum efficiencies of up to 23.1%–31.3% are achieved using these efficient TADF emitters, which are among the most efficient TADF OLEDs ever reported.