Journal
MOLECULES
Volume 26, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/molecules26113128
Keywords
topoisomerase 1; monoterpenoid; cancer; DNA repair enzyme; SAR; molecular modeling; chemical space
Funding
- Russian Scientific Foundation [19-13-00040]
- Russian Science Foundation [19-13-00040] Funding Source: Russian Science Foundation
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Tdp1 is a promising target for anticancer therapy, and new compounds containing specific linkers show inhibitory effects on Tdp1. Some derivatives also work synergistically with topotecan, a Top1 poison, showing sensitizing effects.
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC50 values in the 0.35-0.57 mu M range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC50 (mu M) values were seen from the mid-teens to no effect at 100 mu M. Furthermore, citral derivative 20c, alpha-pinene-derived compounds 20f, 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons.
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