Nucleic acids are important targets for many antitumor drugs [1,2]. They are of particular significance in the medicinal chemistry of certain anticancer agents and gene silencing therapeutics [3]. Apart from the firstly discovered duplex structure nucleic acids may form a number of non-canonical DNA structures (G-quadruplexes [4], i-motifs [5], hairpins [6], triplexes [7] et al.) which play an important role in regulation of biological processes [[8], [9]]. In particular, Gellert and coworkers [10] over 60 years ago discovered that guanine-rich sequences can fold a four-stranded DNA helical secondary structure termed a G-quadruplex (G4). In this structure four guanine bases of the same or different strands form a planar structure (G-quartet or G-tetrad) stabilized by Hoogsteen hydrogen bonds [11]. It is expected that G4s are involved in various cellular processes, such as replication [12], transcription [13], protection of chromosome ends [14], mutagenesis [15], epigenetic processes [16], etc. Interest to quadruplexes arises from the fact that their formation is associated with widespread human diseases (oncological, cardiovascular, neurodegenerative disorders) [[17], [18], [19]]. Moreover, oncological diseases hold a specific place, since the putative quadruplex sequences are found in the promoter regions of human oncogenes expressed in tumor cells or involved in tumor angiogenesis, apoptosis and metastasis: c-MYC [20], K-Ras [21], H-Ras [22], Bcl-2 [23], VEGF [24], c-Kit [25], hTERT [26], HIF-1 [27], etc. In this regard, G4s are promising targets for anticancer therapy.

Over the past 20 years, a large number of small molecules, those are capable to stabilize G4s in telomeric DNA and oncogene promoters, have been discovered [28]. The well-known G4 ligands are based on derivatives of perylene diimide, phenanthroline, acridine, porphyrin, and polyheterocyclic macrocycles [[29], [30], [31]]. Anthraquinone derivatives are also of considerable interest in the search for new compounds targeting different topologies of nucleic acids. Anthraquinone scaffold was a structural unit of first G4 ligands inhibiting telomerase activity [32]. Additionally, anthraquinones fused to the heterocyclic core (heteroarenanthraquinones) have attracted great attention in the past few years. Derivatives of anthra[2,3-b]thiophene-5,10-diones and anthra[2,3-b]furan-5,10-diones were identified as potent G4 binders. For example, compound 1 (Fig. 1) was shown to penetrate into malignant T24 bladder cells, bind to DNA and RNA G-quadruplexes and decrease H-Ras expression [33]. A biotin-streptavidin pull-down assay demonstrated that anthrafuran 2 interacts with RG4s in the K-Ras transcript under low-abundance cellular conditions. Both G4-ligands 2 and 3 (Fig. 1) efficiently penetrate the Panc-1 cells, suppressing protein p21K-Ras [34]. Interestingly, thiophene 4 containing a cyclic amine has an affinity for the DNA duplex [35].

To study an influence of the heterocycle on biological properties, we proposed an original synthesis scheme and investigated the structure-activity relationship (SAR) of previously unknown G4-binders based on heteroarene-fused anthraquinones with three heteroatoms, namely, thiadiazole, selenadiazole and triazole derivatives. In the present work, new agents with high antiproliferative activity were identified, and their ability to bind to G4 structures was proved.