Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells

Stella Cascioferro; Giovanna Li Petri; Barbara Parrino; Daniela Carbone; Niccola Funel; Cecilia Bergonzini; Giulia Mantini; Henk Dekker; Daan Geerke; Godefridus J. Peters; Girolamo Cirrincione; Elisa Giovannetti; Patrizia Diana

doi:10.1016/j.ejmech.2020.112088

Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells

Stella Cascioferro
, Giovanna Li Petri
, Barbara Parrino
, Daniela Carbone
, Niccola Funel
, Cecilia Bergonzini
, Giulia Mantini
, Henk Dekker
, Daan Geerke
, Godefridus J. Peters
, Girolamo Cirrincione
, Elisa Giovannetti
, Patrizia Diana^*

^*Corresponding author for this work

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Research output: Contribution to Journal › Article › Academic › peer-review

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Abstract

A new series of eighteen imidazo [2,1-b] [1,3,4]thiadiazole derivatives was efficiently synthesized and screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. Two out of eighteen derivatives, compounds 12a and 12h, showed remarkably cytotoxic activity with the half maximal inhibitory concentration values (IC₅₀) ranging from 0.23 to 11.4 μM, and 0.29–12.2 μM, respectively. However, two additional compounds, 12b and 13g, displayed remarkable in vitro antiproliferative activity against pancreatic ductal adenocarcinoma (PDAC) cell lines, including immortalized (SUIT-2, Capan-1, Panc-1), primary (PDAC-3) and gemcitabine-resistant (Panc-1R), eliciting IC₅₀ values ranging from micromolar to sub-micromolar level, associated with significant reduction of cell-migration and spheroid shrinkage. These remarkable results might be explained by modulation of key regulators of epithelial-to-mesenchymal transition (EMT), including E-cadherin and vimentin, and inhibition of metalloproteinase-2/-9. High-throughput arrays revealed a significant inhibition of the phosphorylation of 45 tyrosine kinases substrates, whose visualization on Cytoscape highlighted PTK2/FAK as an important hub. Inhibition of phosphorylation of PTK2/FAK was validated as one of the possible mechanisms of action, using a specific ELISA. In conclusion, novel imidazothiadiazoles show potent antiproliferative activity, mediated by modulation of EMT and PTK2/FAK.

Original language	English
Article number	112088
Pages (from-to)	1-18
Number of pages	18
Journal	European Journal of Medicinal Chemistry
Volume	189
Early online date	25 Jan 2020
DOIs	https://doi.org/10.1016/j.ejmech.2020.112088
Publication status	Published - 1 Mar 2020

Funding

This work was partially supported in the collections and analysis of data by the following grants: CCA Foundation 2015 and 2018 grants, KWF Dutch Cancer Society grants (KWF project# 10401 and # 11957 ) and AIRC/Start-Up grant (to E.G.). The Authors would like to thank Btissame El Hassouni, MSc (VUmc, Amsterdam, The Netherlands) for the support with the work on the cell culture experiments.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Antiproliferative activity
Imidazo[2,1-b][1,3,4]thiadiazole derivatives
Inhibition of migration
Modulation of EMT
Pancreatic ductal adenocarcinoma
PTK2/FAK
Spheroids shrinkage

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10.1016/j.ejmech.2020.112088

Imidazo [2,1-b] [1,3,4 ]thiadiazoles with antiproliferative activity against primary and gemcitabineresistant pancreatic cancer cellsFinal published version, 2.11 MBLicence: Article 25fa Dutch Copyright Act

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Cascioferro, S., Petri, G. L., Parrino, B., Carbone, D., Funel, N., Bergonzini, C., Mantini, G., Dekker, H., Geerke, D., Peters, G. J., Cirrincione, G., Giovannetti, E., & Diana, P. (2020). Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells. European Journal of Medicinal Chemistry, 189, 1-18. Article 112088. https://doi.org/10.1016/j.ejmech.2020.112088

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title = "Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells",

abstract = "A new series of eighteen imidazo [2,1-b] [1,3,4]thiadiazole derivatives was efficiently synthesized and screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. Two out of eighteen derivatives, compounds 12a and 12h, showed remarkably cytotoxic activity with the half maximal inhibitory concentration values (IC50) ranging from 0.23 to 11.4 μM, and 0.29–12.2 μM, respectively. However, two additional compounds, 12b and 13g, displayed remarkable in vitro antiproliferative activity against pancreatic ductal adenocarcinoma (PDAC) cell lines, including immortalized (SUIT-2, Capan-1, Panc-1), primary (PDAC-3) and gemcitabine-resistant (Panc-1R), eliciting IC50 values ranging from micromolar to sub-micromolar level, associated with significant reduction of cell-migration and spheroid shrinkage. These remarkable results might be explained by modulation of key regulators of epithelial-to-mesenchymal transition (EMT), including E-cadherin and vimentin, and inhibition of metalloproteinase-2/-9. High-throughput arrays revealed a significant inhibition of the phosphorylation of 45 tyrosine kinases substrates, whose visualization on Cytoscape highlighted PTK2/FAK as an important hub. Inhibition of phosphorylation of PTK2/FAK was validated as one of the possible mechanisms of action, using a specific ELISA. In conclusion, novel imidazothiadiazoles show potent antiproliferative activity, mediated by modulation of EMT and PTK2/FAK.",

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Cascioferro, S, Petri, GL, Parrino, B, Carbone, D, Funel, N, Bergonzini, C, Mantini, G, Dekker, H, Geerke, D, Peters, GJ, Cirrincione, G, Giovannetti, E & Diana, P 2020, 'Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells', European Journal of Medicinal Chemistry, vol. 189, 112088, pp. 1-18. https://doi.org/10.1016/j.ejmech.2020.112088

TY - JOUR

T1 - Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells

AU - Cascioferro, Stella

AU - Petri, Giovanna Li

AU - Parrino, Barbara

AU - Carbone, Daniela

AU - Funel, Niccola

AU - Bergonzini, Cecilia

AU - Mantini, Giulia

AU - Dekker, Henk

AU - Geerke, Daan

AU - Peters, Godefridus J.

AU - Cirrincione, Girolamo

AU - Giovannetti, Elisa

AU - Diana, Patrizia

PY - 2020/3/1

Y1 - 2020/3/1

N2 - A new series of eighteen imidazo [2,1-b] [1,3,4]thiadiazole derivatives was efficiently synthesized and screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. Two out of eighteen derivatives, compounds 12a and 12h, showed remarkably cytotoxic activity with the half maximal inhibitory concentration values (IC50) ranging from 0.23 to 11.4 μM, and 0.29–12.2 μM, respectively. However, two additional compounds, 12b and 13g, displayed remarkable in vitro antiproliferative activity against pancreatic ductal adenocarcinoma (PDAC) cell lines, including immortalized (SUIT-2, Capan-1, Panc-1), primary (PDAC-3) and gemcitabine-resistant (Panc-1R), eliciting IC50 values ranging from micromolar to sub-micromolar level, associated with significant reduction of cell-migration and spheroid shrinkage. These remarkable results might be explained by modulation of key regulators of epithelial-to-mesenchymal transition (EMT), including E-cadherin and vimentin, and inhibition of metalloproteinase-2/-9. High-throughput arrays revealed a significant inhibition of the phosphorylation of 45 tyrosine kinases substrates, whose visualization on Cytoscape highlighted PTK2/FAK as an important hub. Inhibition of phosphorylation of PTK2/FAK was validated as one of the possible mechanisms of action, using a specific ELISA. In conclusion, novel imidazothiadiazoles show potent antiproliferative activity, mediated by modulation of EMT and PTK2/FAK.

AB - A new series of eighteen imidazo [2,1-b] [1,3,4]thiadiazole derivatives was efficiently synthesized and screened for antiproliferative activity against the National Cancer Institute (NCI-60) cell lines panel. Two out of eighteen derivatives, compounds 12a and 12h, showed remarkably cytotoxic activity with the half maximal inhibitory concentration values (IC50) ranging from 0.23 to 11.4 μM, and 0.29–12.2 μM, respectively. However, two additional compounds, 12b and 13g, displayed remarkable in vitro antiproliferative activity against pancreatic ductal adenocarcinoma (PDAC) cell lines, including immortalized (SUIT-2, Capan-1, Panc-1), primary (PDAC-3) and gemcitabine-resistant (Panc-1R), eliciting IC50 values ranging from micromolar to sub-micromolar level, associated with significant reduction of cell-migration and spheroid shrinkage. These remarkable results might be explained by modulation of key regulators of epithelial-to-mesenchymal transition (EMT), including E-cadherin and vimentin, and inhibition of metalloproteinase-2/-9. High-throughput arrays revealed a significant inhibition of the phosphorylation of 45 tyrosine kinases substrates, whose visualization on Cytoscape highlighted PTK2/FAK as an important hub. Inhibition of phosphorylation of PTK2/FAK was validated as one of the possible mechanisms of action, using a specific ELISA. In conclusion, novel imidazothiadiazoles show potent antiproliferative activity, mediated by modulation of EMT and PTK2/FAK.

KW - Antiproliferative activity

KW - Imidazo[2,1-b][1,3,4]thiadiazole derivatives

KW - Inhibition of migration

KW - Modulation of EMT

KW - Pancreatic ductal adenocarcinoma

KW - PTK2/FAK

KW - Spheroids shrinkage

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U2 - 10.1016/j.ejmech.2020.112088

DO - 10.1016/j.ejmech.2020.112088

M3 - Article

C2 - 32007666

AN - SCOPUS:85078487602

SN - 0223-5234

VL - 189

SP - 1

EP - 18

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

M1 - 112088

ER -

Imidazo[2,1-b] [1,3,4]thiadiazoles with antiproliferative activity against primary and gemcitabine-resistant pancreatic cancer cells

Abstract

Funding

UN SDGs

Keywords

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