Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors
Graphical abstract
Introduction
Developing inhibitors of DNA repair enzymes is a promising approach to improve anticancer therapy, particularly for drug-resistant tumors. Radiation and chemotherapy of cancer usually induce DNA lesions; however, tumors can be resistant, or develop resistance, during treatment. Tyrosyl-DNA phosphodiesterase (Tdp1) plays a crucial role in repair of DNA lesions formed by antitumor drugs such as the Top1 inhibitors camptothecin, topotecan and irinotecan, making Tdp1 a promising target for adjunctive cancer treatment.[1], [2], [3] A relatively small number of Tdp1 inhibitors[4], [5], [6], [7], [8], [9], [10], [11], [12], [13] have been reported in literature; most of them exhibit moderate inhibiting activity, which makes discovering novel Tdp1 inhibitors a worthwhile undertaking. Natural products are an important source of compounds for the development of novel medicines, due to the high chemical diversity often lacking in libraries of synthetic molecules.[14], [15] Indeed, a number of effective Tdp1 inhibitors were identified from natural products.[16], [17], [18], [19] It has been previously demonstrated that inhibition of Tdp1 using terpene-coumarin based ligands (see analogue 1, Fig. 1), has a synergistic effect with camptothecin on the viability of the MCF-7 breast cancer cell line.[18], [20]
Usnic acid is a secondary metabolite commonly found in various types of lichens, which has a broad range of biological activities: antiviral, antibiotic, analgesic, antimycotic and insecticide.[21], [22] Research conducted over the past few decades has demonstrated that targeted synthesis of usnic acid derivatives yields various polycyclic compounds that exhibit potent biological activity for a number of important diseases, such as malaria, influenza and tuberculosis.[23], [24], [25]
It has been previously found that usnic acid derivatives, modified at ring C (general structure formula 3, Fig. 1), are effective Tdp1 inhibitors with significant synergistic effect on the viability of the MCF-7 breast cancer cell line.20 However, the presence of the native moieties on ring C is known to be important for the penetration of usnic acid derivatives through biological membranes.26 This study aimed to synthesize and test the Tdp1 inhibitory activity of usnic acid derivatives containing aryl- or hetarylidenfuranone moieties at ring A, keeping the triketone system in ring C of natural dibenzofurane intact.
Section snippets
Chemistry
We have previously proposed the three-step synthesis scheme of benzylidenefuranone derivatives from (+)-usnic acid that included the stage of electrophilic bromination with bromine in dioxane giving bromoderivative 4; subsequent intramolecular cyclization of compound 4 into furanone 5 in the presence of potassium hydroxide; and alkali-catalyzed condensation of 5 with appropriate aldehydes, resulting in compounds 6a-d, 6h-k (Scheme 1).27
Compounds 6a-k, m-z (Table 1) as well as compound 6zz with
Conclusion
Twenty nine usnic acid derivatives 6a-zz, 7m and 7x were synthesized, and evaluated for their in vitro Tdp1 inhibitory activity using a fluorescent based assay, which was verified with a gel-based assay for analogue 6g. It was found that the absolute configuration of the asymmetric center in usnic acid derivatives does not influence inhibitory activity of the compounds.
Compounds 6a-z, 7m and 7x exhibited very high to moderate inhibitory activity (IC50 = 0.025 − 6.7 μM), compared to the
Chemistry
The analytical and spectral studies were conducted in the Chemical Service Center for the collective use of SB RAS.
The 1H and 13C NMR spectra for solutions of the compounds in CDCl3 were recorded on a Bruker AV-400 spectrometer (400.13 and 100.61 MHz, respectively). The residual signals of the solvent were used as references (δH 2.48,δC 39.52). The mass spectra (70 eV) were recorded on a DFS Thermo Scientific high-resolution mass spectrometer. The melting points were measured using a Kofler
Acknowledgments
This work was supported by Russian Science Foundation (grant 16-13-10074), excluding the synthesis of the tyrosine-containing solid support and oligonucleotide, which was funded by Russian Science Foundation (grant 15-15-00121 to D. Stetsenko), and grant of Russian Foundation for Basic Research 16-03-00374 to O. Luzina for synthesis of compound 6zz.
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2020, Bioorganic and Medicinal ChemistryCitation Excerpt :The literature reports on a number of TDP1 inhibitors, with potency varying from submicromolar to millimolar values.20,21 Previously, we found effective TDP1 inhibitors based on usnic acid,22-26 aminoadamantanes,27-29 benzopentathiepines,30 bile acids,31 chromenes,32 thieno[2,3-b]pyridines,33 and coumarin derivatives.34 The combination of some of these inhibitors with camptothecin or its derivative topotecan showed synergistic effect on tumor cell lines.22,23,24,26,34
Insights into the chemistry and therapeutic potential of furanones: A versatile pharmacophore
2019, European Journal of Medicinal ChemistryCitation Excerpt :The synergistic effect of the Tdp1 inhibitors with topotecan, a top1 poison in clinical use, was investigated against two human cell lines, A-549 and HEK-293. Compounds 137 and 138 gave very promising results making them valuable lead compound for the development of potent Tdp1 inhibitors for clinical use [112]. All these reports provide a reference for further research on antitumor drugs based on furanone ring system. (
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Equal contribution.