Drug–DNA Interaction Studies of Acridone-Based Derivatives

Abstract

N10-alkylated 2-bromoacridones are a novel series of potent antitumor compounds. DNA binding studies of these compounds were carried out using spectrophotometric titrations, Circular dichroism (CD) measurements using Calf Thymus DNA (CT DNA). The binding constants were identified at a range of K=0.3 to 3.9×10(5) M(-1) and the percentage of hypochromism from the spectral titrations at 28-54%. This study has identified a compound 9 with the good binding affinity of K=0.39768×10(5) M(-1) with CT DNA. Molecular dynamics (MD) simulations have investigated the changes in structural and dynamic features of native DNA on binding to the active compound 9. All the synthesized compounds have increased the uptake of Vinblastine in MDR KBChR-8-5 cells to an extent of 1.25- to1.9-fold than standard modulator Verapamil of similar concentration. These findings allowed us to draw preliminary conclusions about the structural features of 2-bromoacridones and further chemical enhancement will improve the binding affinity of the acridone derivatives to CT-DNA for better drug-DNA interaction. The molecular modeling studies have shown mechanism of action and the binding modes of the acridones to DNA.

Synthesis of novel gefitinib‐based derivatives and their anticancer activity

“…So to check the DNA interaction properties of newly synthesized compounds absorption titrations with calf thymus (CT) DNA was piloted which is a universally used method. It is a simple colorimetric assay technique to evaluate the binding affinity of small molecules with CT DNA . All the results are depicted in Table and Figure .…”

“…It is a simple colorimetric assay technique to evaluate the binding affinity of small molecules with CT DNA. [24] All the results are depicted in Table 3…”

O-Benzyl-N-(9-acridinyl)hydroxylamines

“…The biological activity of this class of compound was further elucidated to involve a ternary complex with Topoisomerase II. 2 9-Aminoacridines, such as the 9-pyridinylaminoacridines, 3 9-aminomethylacridines, 4 acridones, 5 9-thioacridines, 6 and 9-anilinoacridines 8 have been studied for their ability to intercalate DNA. These, and other, studies have verified that the proposed model of binding is valid; a strong intercalation of the acridine with duplex DNA requires that the intercalator exist as a cation under physiological conditionsm 7 be planar and aromatic, and possess substitution that is directed away from the site of intercalation.…”

Changes in cellular glycosylation of leukemia cells upon treatment with acridone derivatives yield insight into drug action

“…Recently, their antitumor activity has attracted increased attention and a series of new acridone derivatives have been synthesized to test for more effective antitumor activities . Some of these novel acridone derivatives act as topoisomerase inhibitors , DNA intercalators or selective telomeric G‐quadruplex DNA ligands . Antitumor efficacy of acridone derivatives have been examined using several techniques, including mass spectrometry by probing protein–target interactions , fluorescence analysis for DNA binding activity and other traditional molecular biological technologies for protein and gene expressions .…”

“…Taken together our findings suggest that glycosylation is strongly affected by therapeutic potency and can be used as possible biomarkers for monitoring toxicity and antitumor activity of 8a.Abbreviations: CM, cell membrane; GCC, graphitized carbon cartridge; PGC, porous graphitized carbon; WCL, whole cell lysate activities [4]. Some of these novel acridone derivatives act as topoisomerase inhibitors [5], DNA intercalators [6] or selective telomeric G-quadruplex DNA ligands [7]. Antitumor efficacy of acridone derivatives have been examined using several techniques, including mass spectrometry by probing protein-target interactions [8], fluorescence analysis for DNA binding activity [9] and other traditional molecular biological technologies for protein and gene expressions [10].…”