Chemotherapeutic potential of 9-phenyl acridine: biophysical studies on its binding to DNA

Abstract

Acridines and their derivatives are well-known probes for nucleic acids as well as being relevant in the field of drug development to establish new chemotherapeutic agents. We have shown from molecular modelling studies that 9-phenyl acridine and some of its derivatives can act as inhibitors of topoisomerase I and thus have potential to act as anticancer agents. Rational design of new compounds for therapeutics requires knowledge about their structural stability and interactions with various cellular macromolecules. In this regard it is important to know how these molecules would interact with DNA. Here we report the interaction of 9-phenyl acridine (ACPH) with calf thymus DNA (CT-DNA) based on various biophysical and molecular modelling studies. Spectrophotometric studies indicated that ACPH binds to CT-DNA. DNA melting studies revealed that binding of ACPH to CT-DNA resulted in a small increase in melting temperature, which is unlikely in case of classical intercalator; rather, it indicates external binding. Viscosity measurements show that ACPH exhibits groove binding. Competitive binding of ACPH to CT-DNA pre-bound to ethidium bromide (EB) showed slow quenching. Measurement of the binding constant of ACPH by fluorescent intercalator displacement (FID) assay corroborated the notion that there was groove binding. Molecular modelling studies also supported this finding. Results indicate that binding of ACPH is through partial intercalation in the minor groove of DNA.

Spectroscopic and electrochemical study of interactions between DNA and different salts of 1,4-dihydropyridine AV-153

“…To assess the mode of the DNA interaction with the AV-153 salts we have performed a fluorescent intercalator displacement assay. The method is based on the quenching of the enhanced fluorescence of the DNA-EtBr complex by a second ligand (Ghosh et al, 2010). As presented in Fig.…”

New Aryl Derivatives of Acridine with Poly (ADP- Ribose) Polymerase 1 Inhibitory Activity: A Molecular Modeling Approach

“…Particularly important are the derivatives at C 9 position [16,17].The biological activities of phenyl-derivatives at C 9 position were so far less explored. From our earlier works the biological importance of some aryl derivatives of acridine are already documented [18,19] and the antitumor action have been demonstrated in different cancer cell lines as well as in animal model [20]. Aryl acridine derivatives can also potentiate cell killing by other agents (our unpublished results).…”

Unexpected Cyclization of Tritylamines Promoted by Copper Salt through CH and CN Bond Cleavages to Produce Acridine Derivatives

“…This new cyclization appears to involve a mechanistically fascinating copper series of reactions. 9-Phenylacrydine derivatives are also an important class of molecules because of their biological properties, such as DNA intercalation and antitumor activities, [4] as well as their unique optical and electro-and photochemical properties. [5] Although various synthetic methods for acrydines through transition-metal-catalyzed coupling reactions have been recently developed, [6] the present cyclization provides a more simple, straightforward route from readily available substrates.…”

“…Treatment of tris(4-methylphenyl)methylamine (1 b) and tris(4methoxylphenyl)methylamine (1 c) gave the corresponding 3,6-disubstituted 9-arylacridines 2 b and c in 72 and 68 % yield, respectively (entries 1 and 2). Halogenated tritylamines 1 d-f also underwent the cyclization to give acridines 2 d-f, although prolonged reaction times were needed (entries [3][4][5]. Even in the reaction of 1 f, no other product could be detected by GC and GC-MS, although the substrate was completely consumed.…”