The Wnt/beta-catenin pathway is often found deregulated in cancer. beta-catenin is a multifunctional protein with a central role in physiological homeostasis. Its aberrant high expression, regulated by the presence of the Wnt ligand, leads to various diseases including cancer. It acts as both transcriptional co-regulator and an adaptor protein for intracellular adhesion. In more than half of all cancer cases, such as colorectal carcinoma, breast cancer, liver carcinoma, melanoma and leukemia, beta-catenin accumulates within the nucleus or cytoplasm. Specific drugs against this signaling pathway for clinical treatments have not been approved yet. Herein we report compounds with N-Aryl benzenesulfonamide scaffold, able to interfere with the beta-catenin signaling.[1] Previous studies on sulfonamides have highlighted some inconsistencies in terms of structure-activity relationship studies, therefore we decided to further explore this class of Wnt/beta-catenin inhibitors. Starting from the most active derivatives previously reported FH535 (1) and MSAB (2), we synthesized a small test set of compounds (3-13), by changing the substituent at ring A and the position of the ester functional group at the ring B (Chart 1). All new sulfonamides were tested as inhibitors of Wnt/beta-catenin pathway and showed IC50 values ranging from 7.0 to 18.3 µM. In the luciferase-based TOPFlash assay four analogs were more effective than MSAB, used as reference compound. Derivatives with the methoxy, chlorine or trifluoromethyl at position 4 and the ethyl ester at position 4’ showed the highest inhibition of beta-catenin pathway. With the exception of one derivative, the presence of a methoxy or a nitro group had a detrimental effect on the inhibition of beta-catenin. These data suggest that both the substituent and the nature and position of the group at the ring B play key roles in the inhibition of beta-catenin. In particular, two compounds has also been tested for the capability to inhibit colon cancer cell growth by affecting beta-catenin and c-MYC expression levels. References [1] L. Di Magno, F. Di Pastena, M. Puxeddu, G. La Regina, A. Coluccia, A. Ciogli, S. Manetto, M. Maroder, G. Canettieri, R. Silvestri, M. Nalli. ChemMedChem. 2020, 15, 2264.
Novel sulfonamide inhibitors of beta-catenin signaling as anticancer agents / Sebastiani, J.; Coluccia, A.; La Regina, G.; Canettieri, G.; Silvestri, R.. - (2021). (Intervento presentato al convegno XXVII Congresso Nazionale della Società Chimica Italiana tenutosi a Online meeting).
Novel sulfonamide inhibitors of beta-catenin signaling as anticancer agents
Sebastiani, J.;Coluccia, A.;La Regina, G.;Canettieri, G.;Silvestri, R.
2021
Abstract
The Wnt/beta-catenin pathway is often found deregulated in cancer. beta-catenin is a multifunctional protein with a central role in physiological homeostasis. Its aberrant high expression, regulated by the presence of the Wnt ligand, leads to various diseases including cancer. It acts as both transcriptional co-regulator and an adaptor protein for intracellular adhesion. In more than half of all cancer cases, such as colorectal carcinoma, breast cancer, liver carcinoma, melanoma and leukemia, beta-catenin accumulates within the nucleus or cytoplasm. Specific drugs against this signaling pathway for clinical treatments have not been approved yet. Herein we report compounds with N-Aryl benzenesulfonamide scaffold, able to interfere with the beta-catenin signaling.[1] Previous studies on sulfonamides have highlighted some inconsistencies in terms of structure-activity relationship studies, therefore we decided to further explore this class of Wnt/beta-catenin inhibitors. Starting from the most active derivatives previously reported FH535 (1) and MSAB (2), we synthesized a small test set of compounds (3-13), by changing the substituent at ring A and the position of the ester functional group at the ring B (Chart 1). All new sulfonamides were tested as inhibitors of Wnt/beta-catenin pathway and showed IC50 values ranging from 7.0 to 18.3 µM. In the luciferase-based TOPFlash assay four analogs were more effective than MSAB, used as reference compound. Derivatives with the methoxy, chlorine or trifluoromethyl at position 4 and the ethyl ester at position 4’ showed the highest inhibition of beta-catenin pathway. With the exception of one derivative, the presence of a methoxy or a nitro group had a detrimental effect on the inhibition of beta-catenin. These data suggest that both the substituent and the nature and position of the group at the ring B play key roles in the inhibition of beta-catenin. In particular, two compounds has also been tested for the capability to inhibit colon cancer cell growth by affecting beta-catenin and c-MYC expression levels. References [1] L. Di Magno, F. Di Pastena, M. Puxeddu, G. La Regina, A. Coluccia, A. Ciogli, S. Manetto, M. Maroder, G. Canettieri, R. Silvestri, M. Nalli. ChemMedChem. 2020, 15, 2264.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
