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  • br Summary The presented results of the analysis of

    2022-06-18


    Summary The presented results of the analysis of the unfolding of G-quadruplex and i-motif, which may appear within the telomeric DNA region, led to several important conclusions. Namely, determination of the work necessary to unfold of these structures, in biased molecular dynamics involving steered rmsd increase, allowed us to state that G-quadruplexes are highly stable and their stability actually does not depend on the pH which indirectly comes through modification of the energetic state of the complementary i-motif. The unfolding of the G-quadruplex proceeds in quite different way depending on pH, namely at the neutral pH the deterioration starts from G13-G21-G25-G33 guanine quartet while at the acidic one G15-G19-G27-G31 quartet is destroyed first (see Fig. 1). The complementary i-motifs are unaffected by the enforced and strong structural changes in the G-quadruplexes.
    Acknowledgments This work was supported by Polish National Science Centre grant 2017/27/B/ST4/00108.
    Introduction The Guanine-rich nucleic isoquercitrin sale sequences are prevalent in human genes, especially in telomere ends and promoters of some functionally important proto-oncogenes [[1], [2], [3]]. The guanine tracts in these sequences can fold into G-quadruplexes (G4) via Hoogsten hydrogen bonds. There are evidences that G4s are involved in a variety of biological processes [4,5]. Human telomeric DNA consists of tandem repeats of the sequence 5′-d(TTAGGG)-3′, which protects chromosomes from degradation and is essential for ensuring genomic stability. The telomerase is selectively expressed in the majority of human cancer cells, and its activation is thought to be a critical step in cellular immortalization and tumorigenesis. The telomeric G4 stabilizing ligands can inhibit telomerase activity and induce growth arrest in cancer cells [6]. On the other hand, the proto-oncogenes play critical roles in the regulation of programmed cell death or apoptosis. The abnormal overexpress of the proto-oncogenes has recently been shown in tumors. For example, the c-myc proto-oncogene, overexpressed in up to 80% of solid tumors, such as gastrointestinal, ovarian and breast cancer tumors [7,8]. The proto-oncogenes can be transcriptionally repressed by targeting a putative G4 with small molecules [9,10]. A large number of small molecules and metal complexes, such as porphyrin derivatives, carbazole derivatives, quinolines, peptide and Quarfloxin can bind G4s and modulate the gene expression [[11], [12], [13], [14], [15], [16]]. Thus, G4s are considered as a promising new class of targets for the design of anticancer drugs [[17], [18], [19], [20]]. Naphthalimide derivatives, as a class of DNA-binding agents, have been extensively explored as antitumor agents [21]. However, naphthalimide-based anti-tumor drugs may cause serious side effects, including central neurotoxicity and dose-limiting toxicity. In order to improve their potency and reduce the side effects, naphthalimide derivatives, modified with fused aromatic rings, side chains and imide substituents have been synthesized [[22], [23], [24], [25], [26]]. Recently, the studies of the sequence-specific binding of naphthalimides to DNA have been an important topic in the design of novel drugs [27]. The trisubstituted naphthalimide derivatives can bind telomeric G-quadruplexes with high affinity and show antiproliferation activity against various cell lines [28]. We have also synthesized a series of naphthalimides modified with thiourea, imidazole and terpyridine complexes, which possess high affinity (Ka > 106 M−1) and reasonable selectivity for telomeric G-quadruplex DNA over duplex DNA [[29], [30], [31]]. It has been reported that the bisnaphthalimides bisnafide and elinafide present potent cellular cytotoxicity and excellent in vivo antitumor activity, and have been selected for clinical trials [32]. The substituents at naphthalimide skeleton and linkers play crucial roles in determining the sequence selectivity, photophysical properties and cytotoxic activity of bisnaphthalimides derivatives [[33], [34], [35], [36], [37], [38]]. However, to the best of our knowledge, there is no report about the interaction between bisnaphthalimide and G-quadruplexes. In this study, the bisnaphthalimides with alkyl amino linkages are synthesized. The flexible polyamine-bridge can facilitate the electrostatic interactions with the loops and grooves of the phosphate backbone of G4 DNA [39]. The morpholine and 1,2,3-triazole moieties are incorporated at the 4-position of the bisnaphthalene ring to enhance their G4 binding ability and cytotoxic activity [40,41]. The association of bisnaphthalimides with telomeric and oncogenic promoter G4s, including c-myc and c-kit quadruplex, is investigated in detail by spectroscopic techniques and molecular docking studies. Systematic investigation of the interaction between bisnaphthalimde and G4s can provide structural insight into recognition of G-quadruplex by naphthalimides, and can be helpful for the design of G-quadruplex targeting agents.