C-1311 (Symadex), a potential anti-cancer drug, intercalates into DNA between A and G moieties. NMR-derived and MD-refined stereostructure of the d(GAGGCCTC) 2 :C-1311 complex

A strong preference for the TA/TA dinucleotide step discovered for an acridine-based, potent antitumor dsDNA intercalator, C-1305: NMR-driven structural and sequence-specificity studies

“…In the presence of the TA/TA step in the duplex, the alternative intercalation sites were utterly ignored by the ligand. This result was rather surprising, since, considering the previous studies on the closely related imidazoacridinone C-1311, a symmetrical intercalation into the GA/TC steps 15 , 16 was expected. While the experiments reported herein have proven otherwise, in the next step a systematic sequence-specificity study on the triazoloacridinone C-1305 has been initiated, in order to: (1) confirm the binding preference of C-1305 to the TA/TA step in other sequence contexts, (2) examine the CG/CG, GA/TC and AT/AT steps without the presence of the TA/TA step, and finally (3) examine the remaining 6 dinucleotide sequences.…”

“…Unfortunately, the resulting d(CCCGGG) 2 :C-1305 complex turned out to be too weakly interacting and too labile to produce a set of good quality NMR spectra indispensable for structure determination studies (Supplementary Figure S1 ). On the second approach, basing on some previous findings regarding sequence specificity of a closely related pro-drug C-1311 16 , the study was focused on a GA/TC-containing palindromic octamer, expecting that it would be able to produce a symmetrical, DNA:drug 1:2 mol/mol complex. The choice fell on the d(CGATATCG) 2 duplex, from now on referred to as D2 , which is an extended version of the d(CGATCG) 2 and d(CGTACG) 2 duplexes—the standard palindromes widely used in the structural studies on the DNA:drug intercalation complexes 13 , 17 – 19 .…”

“…We believe that the complete understanding of the structural aspects of the dsDNA:C-1305 non-covalent adducts formation is crucial for further, biochemically-oriented studies and for the synthesis of new compounds, potentially exhibiting better pharmacological properties. Our previous studies on a C-1305 analogue-imidazoacridinone C-1311 15,16 have suggested that the apparent lack of sequence-specificity of this drug family might not be the case. Thus, we decided to revisit also this aspect using NMR spectroscopy and molecular dynamics (MD) modelling.…”

c-Myc Protein Level Affected by Unsymmetrical Bisacridines Influences Apoptosis and Senescence Induced in HCT116 Colorectal and H460 Lung Cancer Cells

“…C-1311 reached phase II clinical trials [ 53 ] and has been extensively investigated in various cell lines. Studies have shown that C-1311 is a DNA intercalator and topoisomerase II inhibitor [ 54 ]. It caused the accumulation of cells in the G2/M phase and subsequent induction of apoptosis, necrosis, autophagy, mitotic catastrophe or accelerated senescence, wherein apoptosis was not the main cause of cell death in solid cancer cell lines, especially HCT116 [ 55 ] and H460 cells [ 56 ].…”

Acid–Base Equilibrium and Self-Association in Relation to High Antitumor Activity of Selected Unsymmetrical Bisacridines Established by Extensive Chemometric Analysis

“…Although dimer compounds indeed consist of an imidazoacridinone and 1-nitroacridine monomer connected by a flexible linker, their properties are by no means a simple sum of characteristics displayed by monomeric compounds. For instance, acridine monomers have been shown to directly interact with DNA, which was confirmed by up to a 20-degree increase in the delta T m of the double-stranded DNA helix [13,14]. However, our preliminary studies revealed that UAs increased this parameter by merely 5-7 degrees, which suggests non-specific interactions between UAs and the DNA helix [1].…”