Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors

Zakharova, Olga D.; Luzina, O. A.; Zakharenko, Alexandra L.; Sokolov, D. N.; Filimonov, Aleksandr; Dyrkheeva, Nadezhda S.; Chepanova, Arina A; Ilina, E. S.; Ilyina, A. P.; Klabenkova, Kristina; Челобанов, Б. П.; Stetsenko, Dmitry A.; Zafar, Ayesha; Eurtivong, Chatchakorn; Reynisson, Jóhannes; Волчо, К. П.; Salakhutdinov, N. F.; Lavrik, Olga I.

doi:10.1016/j.bmc.2018.07.039

Cited by 30 publications

(40 citation statements)

References 47 publications

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“…2-fold increase in cytotoxicity of the drug when administered with the compound 6x) ( Table 1). Interestingly, the authors did not observe a correlation between the UA derivatives' activity against a pure enzyme and their cytotoxicity and ability to enhance the topotecan effect, which was explained by possible existence of substrates other than TDP1 in the cancer cells [47].…”

Section: Synthesis/semisynthesis Of Ua Derivatives With Improved Antimentioning

confidence: 90%

“…As the presence of native substituents in the C ring is important for penetration of UA derivatives through biological membranes [39•], in further research, 29 UA derivatives were synthesised with an intact C ring, but with aryl or heteroarylidenfuranone moieties at the A ring [47]. Among them, 5-bromothiophen-2-yl UA derivative 6× (Fig.…”

Section: Synthesis/semisynthesis Of Ua Derivatives With Improved Antimentioning

confidence: 99%

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Usnic Acid Derivatives as Cytotoxic Agents Against Cancer Cells and the Mechanisms of Their Activity

2019

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Purpose of Review This article summarises recent research on modifications of the structure or formula of usnic acid (UA), a lichen secondary metabolite, in order to obtain derivatives with higher bioavailability, potency and selectivity against cancer cells and presents the current knowledge on the mechanisms of action of such compounds. Recent Findings Numerous approaches have been undertaken to improve bioactivity of UA concerning its use as an anticancer drug. Among them, the synthesis of UA salts or complexation with 2-hydroxypropyl-β-cyclodextrin to improve its solubility and the encapsulation using different carriers (including various nanomaterials) to stabilise UA in biological fluids and improve their penetrance to, and release in, cancer cells were applied.. Synthetic modification of the UA structure has been explored to obtain more active and cancer-specific derivatives. Recent work indicates that some modifications of the C or A ring of UA selectively increase its antiproliferative potential against cancer cells. Moreover, specific changes in the UA structure allow to obtain derivatives which inhibit enzymes important for the cancer cells' survival, such as mTOR, Pim, TDP1 or PARP. Some of them have been shown to enhance anticancer activity of the already approved chemotherapeutics, such as topotecan. Others, when used in an animal cancer xenograft model, were superior to UA in retardation of tumour growth and less toxic that the parent compound. Summary UA is a promising lead compound for synthesis of anticancer drugs. Further work on its modifications, mechanisms of activity and validation in animal models is critical for development of effective therapeutics.

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Section: Synthesis/semisynthesis Of Ua Derivatives With Improved Antimentioning

confidence: 90%

Section: Synthesis/semisynthesis Of Ua Derivatives With Improved Antimentioning

confidence: 99%

Usnic Acid Derivatives as Cytotoxic Agents Against Cancer Cells and the Mechanisms of Their Activity

2019

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“…A , UA structure B , Enamines of UA 8 . C , Aryliden‐ ( 6 × ) derivative of UA . D , Hydrazinothiazole derivative 20d .…”

Section: Tdp1 Inhibitors: Sensitizing Tumors To Camptothecin and Its mentioning

confidence: 99%

“…However, the presence of native substituents in ring C (Figure B) is important for the penetration of UA derivatives through biological membranes . Therefore, we previously synthesized UA derivatives containing aryliden‐ or hetarylidenfuranone moieties at ring A, keeping the triketone system in ring C of the native dibenzofurane scaffold intact (Figure C, D) . Resultant arylidenfuranone compounds exhibited very high to moderate Tdp1 inhibitory activity (IC 50 = 0.025 ‐ 6.7 μM) and moderate intrinsic cytotoxicity.…”

Section: Tdp1 Inhibitors: Sensitizing Tumors To Camptothecin and Its mentioning

confidence: 99%

“…81 Therefore, we previously synthesized UA derivatives containing aryliden-or hetarylidenfuranone moieties at ring A, keeping the triketone system in ring C of the native dibenzofurane scaffold intact ( Figure 11C, D). 77 Resultant arylidenfuranone compounds exhibited very high to moderate Tdp1 inhibitory activity (IC 50 = 0.025 -6.7 μM) and moderate intrinsic cytotoxicity. Computer modeling revealed that these compounds form lipophilic contacts with the catalytic residue His493 and hydrogen bonds with His263 as well as interact with other amino acid residues of the active site.…”

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confidence: 94%

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Dual DNA topoisomerase 1 and tyrosyl‐DNA phosphodiesterase 1 inhibition for improved anticancer activity

Zakharenko

Dyrkheeva

Lavrik

2019

Medicinal Research Reviews

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Tyrosyl‐DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme that catalyzes the hydrolysis of the phosphodiester bond in the DNA‐topoisomerase 1 (Top1) covalent complex and repairs some other 3′‐end DNA adducts. Currently, Tdp1 functions as an important target in cancer drug design owing to its ability to break down various DNA adducts induced by chemotherapeutics. Tdp1 inhibitors may sensitize tumor cells to the action of Top1 poisons, thereby potentiating their effects. This mini‐review summarizes findings from studies reporting the combined inhibition of Top1 and Tdp1. Two different approaches have been considered for developing such drug precursors.

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Synthesis and Biological Activities of 11‐ and 12‐Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB and Tyrosyl‐DNA Phosphodiesterase 1 Inhibitors

Yang

Qin

et al. 2023

ChemMedChem

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Herein, a series of 11‐ or 12‐substituted benzophenanthridinone derivatives was designed and synthesized for the discovery of dual topoisomerase IB (TOP1) and tyrosyl‐DNA phosphodiesterase 1 (TDP1) inhibitors. Enzyme‐based assays indicated that two compounds 12 and 38 showed high TOP1 inhibitory potency (+++), and four compounds 35, 37, 39 and 43 showed good TDP1 inhibition with IC50 values ranging from 10 to 18 μM. 38 could induce cellular TOP1cc formation, resulting in the highest cytotoxicity against HCT‐116 cells (0.25 μM). The most potent TDP1 inhibitor 43 (10 μM) could induce cellular TDP1cc formation and enhance topotecan‐induced DNA damage and showed strong synergistic cytotoxicity with topotecan in both MCF‐7 and MCF‐7/TDP1 cells.

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Synthesis and evaluation of aryliden- and hetarylidenfuranone derivatives of usnic acid as highly potent Tdp1 inhibitors

Cited by 30 publications

References 47 publications

Usnic Acid Derivatives as Cytotoxic Agents Against Cancer Cells and the Mechanisms of Their Activity

Usnic Acid Derivatives as Cytotoxic Agents Against Cancer Cells and the Mechanisms of Their Activity

Dual DNA topoisomerase 1 and tyrosyl‐DNA phosphodiesterase 1 inhibition for improved anticancer activity

Synthesis and Biological Activities of 11‐ and 12‐Substituted Benzophenanthridinone Derivatives as DNA Topoisomerase IB and Tyrosyl‐DNA Phosphodiesterase 1 Inhibitors

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