Research paperNew anthra[2,3-b]furancarboxamides: A role of positioning of the carboxamide moiety in antitumor properties
Graphical abstract
Introduction
Since the discovery in 1970s the anthraquinone (anthracene-9,10-dione) containing antitumor drugs keep proving their exceptional clinical value. These drugs are used in a variety of chemotherapeutic regimens including solid and hematological malignancies, with clinical drugs doxorubicin (Dox, Fig. 1A), mitoxantrone, idarubicin and valrubicin as the most significant achievements [[1], [2], [3]]. Molecular determinants of tumor cell death/survival in the presence of anthraquinones are the ATP binding cassette transporters (multidrug resistance (MDR) mediated by the MDR1/P-glycoprotein (Pgp) as a prototypic mechanism) and the drug-DNA interaction sensed largely (but not exclusively) by p53 pathways. Although eventually more mechanisms have been implicated, such as mitochondrial metabolism and modulation of protein kinases [[4], [5], [6], [7]], Pgp-mediated MDR and DNA binding are considered the key factors for screening of new anthraquinone based chemotypes.
Researchers worldwide as well as our group have developed a series of derivatives in which different side chain moieties were conjugated to the anthraquinone scaffold [[8], [9], [10], [11], [12], [13]]. Two major prerequisites for the new compound were considered taking into account Dox as a reference drug: 1) the retained submicromolar cytotoxicity; 2) potency against MDR sublines and cells with a non-functional p53, the mechanisms that limit Dox efficacy.
In particular, heteroarene-fused anthraquinones represent a promising class for antitumor drug development due to circumvention of drug resistance phenotypes, multiple targeting of tumor survival mechanisms, and favorable pharmacological profile [8]. To dissect the role of side chains with cationic groups, a series of anthraquinone congeners fused with pyrrole, thiophene and furan has been developed. Of special interest are anthra[2,3-b]furan-5,10-diones capable of inducing tumor cell death via targeting topoisomerases 1 and 2 (Top 1, 2), G-quadruplexes in nucleic acids, Sirtuin 1, tumor-associated NADH oxidase, and protein kinases [[14], [15], [16], [17]]. Furthermore, anthra[2,3-b]furan-3-carboxamides represent an attractive scaffold for further optimization since its derivatives demonstrated an in vivo therapeutic efficacy against Р388 leukemia, its variant Р388/ADR, and B16/F10 melanoma models [16,18,19]. The analysis of structure-activity relationship (SAR) revealed that 4,11-hydroxy groups, a carbonyl spacer of the amide moiety, as well as a cyclic diamine, constitute the crucial structural elements mechanistically associated with anticancer activity (Fig. 1B) [19]. In addition, (S)-3-aminopyrrolidine at the side chain (compounds 1 and 2) has been proved the preferred substituent in the series demonstrating a superior anticancer activity and a lower general toxicity than (R)-isomer [16,18,19].
In further analysis of structural modifications of anthraquinones, we addressed the role of the positioning of an individual moiety in the side chain(s). We synthesized a series of anthra[2,3-b]furan-5,10-diones bearing the carboxamide fragment at the position 2 of the furan ring. Comparison with the previously reported anthra[2,3-b]furan-3-carboxamide 1 revealed that spatial positioning of the carboxamide moiety relative to the anthrafuran core may significantly change intracellular localization, interaction with targets, and cytotoxicity profiles.
Section snippets
Chemistry
To synthesize the isomeric anthra[2,3-b]furancarboxamides containing the pharmacophore at the position 2, a two step transformation of 4,11-dimethoxy-5,10-dioxoanthra[2,3-b]furan-2-carboxylic acid 3 [20] was developed (Scheme 1). Heating of methoxy derivatives of anthraquinones with a concentrated sulphuric acid at 90–100 °C, as well as treatment with HBr in acetic acid have been demonstrated to be efficient methods for cleavage of methyl ethers [21]. Thus, reflux of 3 in 33% HBr in AcOH led to
Conclusion
We demonstrated differential properties of new anthraquinone derivatives depending on spatial positioning of the carboxamide fragment relative to the furan ring. These findings indicated that the diversity and complexity of antitumor effects evoked by anthraquinone based drugs can be achieved via structural modifications (regioisomerization) in the side chains. Differential potency of anthra[2,3-b]furancarboxamides for cell lines of various species and tissue origin expands the antitumor
Instruments and general information
NMR spectra were recorded on a Varian VXR-400 instrument operated at 400 MHz (1H NMR) and 100 MHz (13C NMR). Chemical shifts were measured in DMSO‑d6, using tetramethylsilane as an internal standard. Analytical TLC was performed on Silica Gel F254 plates (Merck), column chromatography with a SilicaGel Merck 60. Melting points were determined using a Buchi SMP-20 apparatus and are uncorrected. High resolution mass spectra were recorded with electron spray ionization on a Bruker Daltonics
Author contributions
The study was conceived and written by AST, VBT, AES and AAS. AES and AST designed and synthesized the compounds, YLV, LGD, VVT, DNK, AMM, MMM and AKI performed biological experiments, VBT did molecular modeling. All authors approved the final version of the manuscript.
Acknowledgments
We are grateful to Yu.N. Luzikov (deceased), A.M. Korolev and N.M. Malyutina for NMR, HRMS and HPLC studies. The study was funded in part by the Russian Science Foundation (project 18-73-00256 to AST, chemical synthesis) and the Ministry of Science and Higher Education of the Russian Federation in the framework of Increase Competitiveness Program of MISiS (#P02-2017-2-1 to VVT, biology studies).
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2021, European Journal of Medicinal ChemistryCitation Excerpt :In contrast, under the same culture conditions 2 killed only the suspension cell lines including K562 and K562/4 (Table 3). None of the tested adherent cell lines such as HeLa, HCT116, HCT116p53KO, B16, C6, MCF7 and MCF7Dox were sensitive to 2 (IC50 > 50 μM) [18]. Differential potency of 8 vs 2 was further demonstrated in the analysis of cell cycle distribution of K562 cells.