Tyrosyl-DNA Phosphodiesterase 1 Inhibitors: Usnic Acid Enamines Enhance the Cytotoxic Effect of Camptothecin

Zakharenko, Alexandra L.; Luzina, O. A.; Koval, Olga; Nilov, Dmitry K.; Gushchina, Irina V.; Dyrkheeva, Nadezhda S.; Švedas, Vytas K.; Salakhutdinov, N. F.; Lavrik, Olga I.

doi:10.1021/acs.jnatprod.6b00979

Cited by 72 publications

(77 citation statements)

References 49 publications

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“…Importantly, this was not a cell line-specific effect, as this compound also sensitised the A-549 lung cancer cells to the drug (3.5-fold enhancement) ( Table 1). Interestingly, the authors did not observe a significant difference in activity of the stereoisomers of UA derivatives [46].…”

Section: Synthesis/semisynthesis Of Ua Derivatives With Improved Antimentioning

confidence: 87%

“…The Olga Lavrik group had synthesised a series of (+) and (−)-UA enamines and shown that some of them (those with a bulky aromatic substituent at the C ring, such as 3,5-di-tertbutyl-4-hydroxyphenyl, 4-hydroxyphenyl or halogenated phenyl derivatives; Fig. 1, compounds D-G) potently inhibited the tyrosyl-DNA phosphodiesterase I (TDP1) [46]. This enzyme is engaged in processing 3′-lesions in DNA, which are generated, among others, during inhibition of topoisomerase I (Top1), when Top1-DNA covalent complexes are formed.…”

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: 87%

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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“…Enamine substituted UA derivatives (Figure B, Table ) demonstrated Tdp1 inhibitory activity at low micromolar concentrations of 0.15–2 μM . These derivatives showed low intrinsic cytotoxicity and enhanced the effect of topotecan on cancer cells by a factor of 10 to 12 . The molecular modeling of UA enamines with Tdp1 showed that they preferentially bind to a phosphohistidine intermediate rather than to the apo form or enzyme‐substrate complex.…”

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

confidence: 99%

“…Structures of Tdp1 inhibitors – UA derivatives. A , UA structure B , Enamines of UA 8 . C , Aryliden‐ ( 6 × ) derivative of UA .…”

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

confidence: 99%

“…83 These derivatives showed low intrinsic cytotoxicity and enhanced the effect of topotecan on cancer cells by a factor of 10 to 12. 83 The molecular modeling of UA enamines with Tdp1 showed that they preferentially bind to a phosphohistidine intermediate rather than to the apo form or enzymesubstrate complex. We hypothesize that enamine inhibitors in a ternary complex with Tdp1 affect conformations of the residues located at the boundary between the active site and the inhibitor cavity, thus disrupting reactive orientations of the phosphohistidine intermediate and water molecule.…”

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confidence: 99%

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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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Tyrosyl-DNA Phosphodiesterase 1 Inhibitors: Usnic Acid Enamines Enhance the Cytotoxic Effect of Camptothecin

Cited by 72 publications

References 49 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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