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Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Synthesis and investigation of thieno[2,3-b]pyridines that restore activity of topotecan
Emily K Paulin1, Natalie A Haverkate1, Petr Tomek2,3
1School of Chemical Sciences, University of Auckland Auckland 1010 New Zealand lisa.pilkington@auckland.ac.nz d.barker@auckland.ac.nz +64 9 373 7599.
Abstract:
Chemoresistance poses a major challenge to the successful outcome of cancer chemotherapy by reducing or eliminating drug efficacy. Anti-cancer medicines causing DNA damage by inhibiting topoisomerase I (TOP1) are particularly susceptible as cancers adopt resistance mechanisms. Drugs countering these resistance mechanisms can be introduced to the regimen and increase the vulnerability of cancer cells to TOP1 inhibitors. DNA repair enzymes such as tyrosyl-DNA phosphodiesterase 1 (TDP1) emerge as promising drug targets for restoring activity of TOP1 inhibitors. Herein, we describe the synthesis and biological evaluation of thieno[2,3-b]pyridines that markedly sensitised H460 lung cancer cells to the TOP1 inhibitor topotecan. Surprisingly, TDP1 knockout further potentiated the synergy between thieno[2,3-b]pyridines and topotecan suggesting that a complex network of DNA repair pathways rather than TDP1 alone mediates the sensitising effect. SAR studies have identified structural motifs in this compound class that led to optimal performance, identifying leads for development into clinical chemosensitisers of TOP1 poisons.
Insights
New thieno[2,3-b]pyridines sensitize lung cancer cells to topoisomerase I (TOP1) inhibitors like topotecan. This suggests targeting DNA repair pathways, not just TDP1, can overcome chemoresistance.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Chemoresistance reduces the efficacy of anti-cancer drugs, particularly topoisomerase I (TOP1) inhibitors.
- Developing strategies to overcome chemoresistance is crucial for improving cancer treatment outcomes.
- Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a potential target for restoring sensitivity to TOP1 inhibitors.
Purpose of the Study:
- To synthesize and evaluate thieno[2,3-b]pyridines as chemosensitizers for lung cancer.
- To investigate the role of TDP1 in the sensitizing effect of these compounds.
- To identify structure-activity relationships (SAR) for optimizing chemosensitizer development.
Main Methods:
- Synthesis of novel thieno[2,3-b]pyridine derivatives.
- Biological evaluation of synthesized compounds in H460 lung cancer cells.
- Assessment of drug synergy with topotecan in wild-type and TDP1 knockout cells.
- Structure-activity relationship studies.
Main Results:
- Thieno[2,3-b]pyridines significantly sensitized H460 lung cancer cells to topotecan.
- TDP1 knockout cells showed enhanced synergy, indicating a broader DNA repair network involvement.
- SAR studies identified key structural features for potent chemosensitization.
Conclusions:
- Thieno[2,3-b]pyridines are effective chemosensitizers against TOP1 inhibitor resistance in lung cancer.
- The mechanism of sensitization involves a complex interplay of DNA repair pathways beyond TDP1.
- These compounds represent promising leads for developing novel clinical chemosensitizers.
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