Specific stabilization of promoter G-Quadruplex DNA by 2,6-disubstituted amidoanthracene-9,10-dione based dimeric distamycin analogues and their selective cancer cell cytotoxicity

• Published in: European journal of medicinal chemistry 2020-06, Vol.195, p.112202, Article 112202
• Main Authors: Roy, Soma, Ali, Asfa, Kamra, Mohini, Muniyappa, Kalappa, Bhattacharya, Santanu
• Format: Article
• Language: English
• Subjects: Anthracenes - chemistry; Anthraquinone derivatives; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cancer cells; Cytotoxicity; Dimerization; Distamycins - chemistry; Distamycins - pharmacology; DNA - chemistry; DNA - genetics; Drug Design; G-quadruplex DNA; G-Quadruplexes - drug effects; Models, Molecular; Oligopyrrole carboxamides; Polymerase stop assay; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins c-myc - genetics; Telomeric and promoter DNA
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2020.112202

We have designed and synthesized anthraquinone containing compounds which have oligopyrrole side chains of varying lengths. These compounds stabilized the G-quadruplex DNA formed in the promoter regions of c-MYC oncogenes selectively over the duplex DNA. These observations were recorded using UV–vis spectroscopic titrations, fluorescence measurements and circular dichroism (CD) spectral titrations. The potency of the compounds to stabilize the G4 DNA has been shown from the thermal denaturation experiments. The compound interacts with c-MYC G-quadruplex DNA through stacking mode as obtained from ethidium bromide displacement assay, cyclic voltammetric titration, and docking experiments. Molecular modeling studies suggested that the stacking of the anthraquinone moiety over the G-tetrad of the G4 structures are responsible for the stability of such quadruplex secondary structure. Furthermore, polymerase stop assay also supported the formation of stable G4 structures in the presence of the above-mentioned compounds. The compounds have shown selective cancer cell (HeLa and HEK293T) cytotoxicity over normal cells (NIH3T3 and HDFa) under in vitro conditions as determined from MTT based cell viability assay. Apoptosis was found to be the mechanistic pathway underlying the cancer cell cytotoxicity as obtained from Annexin V-FITC and PI dual staining assay which was further substantiated by nuclear morphological changes as observed by AO/EB dual staining assay. Cellular morphological changes, as well as nuclear condensation and fragmentation upon treatment with these compounds, were observed under bright field and confocal microscopy. [Display omitted] •Oligopyrrole carboxamides conjugated anthraquinone derivatives stabilize G-quadruplex DNA over duplex DNA.•Oligopyrrole carboxamides conjugated anthraquinone derivatives stabilize promoter G-quadruplex DNA.•Stacking mode of interaction of the ligand with c-MYC G-quadruplex DNA.•Selective cancer cell cytotoxicity over normal cells was obtained upon treatment of these ligands.•Cellular morphological changes and nuclear condensation observed in the ligand treated cells.