Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments
نویسندگان
چکیده
Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability counter the effects topoisomerase (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 tested against Tdp1. All derivatives exhibited inhibition at low micromolar nanomolar concentrations with most potent inhibitors having IC50 values in 0.35–0.57 µM range. The cytotoxicity was determined HeLa, HCT-116 SW837 cancer cell lines; moderate CC50 (µM) seen from mid-teens no effect 100 µM. Furthermore, citral derivative 20c, α-pinene-derived compounds 20f, 20g 25c, citronellic acid 25b found have sensitizing conjunction topotecan HeLa cervical colon adenocarcinoma lines. ligands are predicted bind catalytic pocket of Tdp1 favorable physicochemical properties further development potential adjunct Top1 poisons.
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ژورنال
عنوان ژورنال: Molecules
سال: 2021
ISSN: ['1420-3049']
DOI: https://doi.org/10.3390/molecules26113128