New Hybrid Compounds Combining Fragments of Usnic Acid and Thioether Are Inhibitors of Human Enzymes TDP1, TDP2 and PARP1

Tyrosyl-DNA phosphodiesterase 1 (TDP1) catalyzes the cleavage of the phosphodiester bond between the tyrosine residue of topoisomerase 1 (TOP1) and the 3′ phosphate of DNA in the single-strand break generated by TOP1. TDP1 promotes the cleavage of the stable DNA–TOP1 complexes with the TOP1 inhibitor topotecan, which is a clinically used anticancer drug. This article reports the synthesis and study of usnic acid thioether and sulfoxide derivatives that efficiently suppress TDP1 activity, with IC50 values in the 1.4–25.2 μM range. The structure of the heterocyclic substituent introduced into the dibenzofuran core affects the TDP1 inhibitory efficiency of the compounds. A five-membered heterocyclic fragment was shown to be most pharmacophoric among the others. Sulfoxide derivatives were less cytotoxic than their thioester analogs. We observed an uncompetitive type of inhibition for the four most effective inhibitors of TDP1. The anticancer effect of TOP1 inhibitors can be enhanced by the simultaneous inhibition of PARP1, TDP1, and TDP2. Some of the compounds inhibited not only TDP1 but also TDP2 and/or PARP1, but at significantly higher concentration ranges than TDP1. Leader compound 10a showed promising synergy on HeLa cells in conjunction with the TOP1 inhibitor topotecan.

Download Full-text

Inhibitory Effect of New Semisynthetic Usnic Acid Derivatives on Human Tyrosyl-DNA Phosphodiesterase 1

Planta Medica ◽

10.1055/a-0681-7069 ◽

2018 ◽

Vol 85 (02) ◽

pp. 103-111 ◽

Cited By ~ 6

Author(s):

Nadezhda Dyrkheeva ◽

Olga Luzina ◽

Aleksandr Filimonov ◽

Olga Zakharova ◽

Ekaterina Ilina ◽

...

Keyword(s):

Biological Activity ◽

Usnic Acid ◽

Inhibitory Effect ◽

Repair Enzyme ◽

Topoisomerase 1 ◽

Anticancer Properties ◽

Human Dna ◽

Whole Number ◽

Ic50 Values ◽

Low Cytotoxicity

AbstractUsnic acid, a lichen secondary metabolite produced by a whole number of lichens, has attracted the interest of researchers owing to its broad range of biological activity, including antiviral, antibiotic, anticancer properties, and it possessing a certain toxicity. The synthesis of new usnic acid derivatives and the investigation of their biological activity may lead to the discovery of compounds with better pharmacological and toxicity profiles. In this context, a series of new usnic acid derivatives comprising a terpenoid moiety were synthesized, and their ability to inhibit the catalytic activity of the human DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 was investigated. The most potent compounds (15a, 15b, 15g, and 16a, 16b, 16g) had IC50 values in the range of 0.33 – 2.7 µM. The inhibitory properties were mainly dependent on the flexibility and length of the terpenoid moiety, but not strongly dependent on the configuration of the asymmetric centers. The synthesized derivatives showed low cytotoxicity against human cell lines in an MTT assay. They could be used as a basis for the development of more effective anticancer therapies when combined with topoisomerase 1 inhibitors.

Download Full-text

New Hybrid Compounds Combining Fragments of Usnic Acid and Monoterpenoids for Effective Tyrosyl-DNA Phosphodiesterase 1 Inhibition

Biomolecules ◽

10.3390/biom11070973 ◽

2021 ◽

Vol 11 (7) ◽

pp. 973

Author(s):

Nadezhda S. Dyrkheeva ◽

Aleksandr S. Filimonov ◽

Olga A. Luzina ◽

Alexandra L. Zakharenko ◽

Ekaterina S. Ilina ◽

...

Keyword(s):

Cell Lines ◽

Anticancer Agents ◽

Biological Activities ◽

Usnic Acid ◽

Topoisomerase 1 ◽

Binding Domains ◽

Promising Therapeutic Target ◽

Wide Range ◽

Ic50 Values ◽

Low Cytotoxicity

Usnic acid (UA) is a secondary metabolite of lichens that exhibits a wide range of biological activities. Previously, we found that UA derivatives are effective inhibitors of tyrosyl-DNA phosphodiesterase 1 (TDP1). It can remove covalent complex DNA-topoisomerase 1 (TOP1) stabilized by the TOP1 inhibitor topotecan, neutralizing the effect of the drugs. TDP1 removes damage at the 3′ end of DNA caused by other anticancer agents. Thus, TDP1 is a promising therapeutic target for the development of drug combinations with topotecan, as well as other drugs for cancer treatment. Ten new UA enamino derivatives with variation in the terpene fragment and substituent of the UA backbone were synthesized and tested as TDP1 inhibitors. Four compounds, 11a-d, had IC50 values in the 0.23–0.40 μM range. Molecular modelling showed that 11a-d, with relatively short aliphatic chains, fit to the important binding domains. The intrinsic cytotoxicity of 11a-d was tested on two human cell lines. The compounds had low cytotoxicity with CC50 ≥ 60 μM for both cell lines. 11a and 11c had high inhibition efficacy and low cytotoxicity, and they enhanced topotecan’s cytotoxicity in cancerous HeLa cells but reduced it in the non-cancerous HEK293A cells. This “protective” effect from topotecan on non-cancerous cells requires further investigation.

Download Full-text

Electron induced single strand break and cyclization: a DFT study on the radiosensitization mechanism of the nucleotide of 8-bromoguanine

Physical Chemistry Chemical Physics ◽

10.1039/c3cp55411b ◽

2014 ◽

Vol 16 (14) ◽

pp. 6568-6574 ◽

Cited By ~ 13

Author(s):

Lidia Chomicz ◽

Al'ona Furmanchuk ◽

Jerzy Leszczynski ◽

Janusz Rak

Keyword(s):

Electron Attachment ◽

Strand Break ◽

Single Strand ◽

Dft Study ◽

Single Strand Break ◽

Phosphodiester Bond ◽

Bond Breakage

The radiosensitization mechanism of 8-bromoguanosine is studied on its 3′,5′-diphosphate. Electron attachment to the nucleotide results in phosphodiester bond breakage or the 5′,8-cycloguanosine lesion.

Download Full-text

Topoisomerase 1 and Single-Strand Break Repair Modulate Transcription-Induced CAG Repeat Contraction in Human Cells

Molecular and Cellular Biology ◽

10.1128/mcb.05158-11 ◽

2011 ◽

Vol 31 (15) ◽

pp. 3105-3112 ◽

Cited By ~ 36

Author(s):

L. Hubert ◽

Y. Lin ◽

V. Dion ◽

J. H. Wilson

Keyword(s):

Strand Break ◽

Human Cells ◽

Single Strand ◽

Cag Repeat ◽

Single Strand Break ◽

Topoisomerase 1 ◽

Single Strand Break Repair ◽

Break Repair

Download Full-text

Activated STAT3 Is a Novel Regulator of the XRCC1 Promoter and Selectively Increases XRCC1 Protein Levels in Triple Negative Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22115475 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5475

Author(s):

Griffin Wright ◽

Manoj Sonavane ◽

Natalie R. Gassman

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Excision Repair ◽

Strand Break ◽

Xrcc1 Gene ◽

Single Strand Break ◽

Expression Levels ◽

Constitutive Activation ◽

Gene And Protein Expression

Base Excision Repair (BER) addresses base lesions and abasic sites induced by exogenous and endogenous stressors. X-ray cross complementing group 1 (XRCC1) functions as a scaffold protein in BER and single-strand break repair (SSBR), facilitating and coordinating repair through its interaction with a host of critical repair proteins. Alterations of XRCC1 protein and gene expression levels are observed in many cancers, including colorectal, ovarian, and breast cancer. While increases in the expression level of XRCC1 are reported, the transcription factors responsible for this up-regulation are not known. In this study, we identify the signal transducer and activator of transcription 3 (STAT3) as a novel regulator of XRCC1 through chromatin immunoprecipitation. Activation of STAT3 through phosphorylation at Y705 by cytokine (IL-6) signaling increases the expression of XRCC1 and the occupancy of STAT3 within the XRCC1 promoter. In triple negative breast cancer, the constitutive activation of STAT3 upregulates XRCC1 gene and protein expression levels. Increased expression of XRCC1 is associated with aggressiveness and resistance to DNA damaging chemotherapeutics. Thus, we propose that activated STAT3 regulates XRCC1 under stress and growth conditions, but constitutive activation in cancers results in dysregulation of XRCC1 and subsequently BER and SSBR.

Download Full-text