Novel Tdp1 Inhibitors Based on Adamantane Connected with Monoterpene Moieties via Heterocyclic Fragments

Molecules. 2021 May 24;26(11):3128. doi: 10.3390/molecules26113128.


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 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC50 (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative 20c, α-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.

Keywords: DNA repair enzyme; SAR; cancer; chemical space; molecular modeling; monoterpenoid; topoisomerase 1.

MeSH terms

  • Adamantane / chemistry
  • Adamantane / pharmacology*
  • Carbon-13 Magnetic Resonance Spectroscopy
  • Cell Line, Tumor
  • Humans
  • Ligands
  • Mass Spectrometry
  • Monoterpenes / chemistry*
  • Phosphoric Diester Hydrolases / drug effects*
  • Proton Magnetic Resonance Spectroscopy
  • Structure-Activity Relationship


  • Ligands
  • Monoterpenes
  • Phosphoric Diester Hydrolases
  • TDP1 protein, human
  • Adamantane