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

被引：59

作者：

Cascioferro, Stella ^{[1
]}

Petri, Giovanna Li ^{[1
,2
]}

Parrino, Barbara ^{[1
]}

Carbone, Daniela ^{[1
]}

Funel, Niccola ^{[3
]}

Bergonzini, Cecilia ^{[2
]}

Mantini, Giulia ^{[2
]}

Dekker, Henk ^{[2
]}

Geerke, Daan ^{[4
]}

Peters, Godefridus J. ^{[2
]}

Cirrincione, Girolamo ^{[1
]}

Giovannetti, Elisa ^{[2
,5
]}

Diana, Patrizia ^{[1
]}

机构：

[1] Univ Palermo, Dipartimento Sci & Tecnol Biol Chim & Farmaceut S, Via Archirafi 32, I-90123 Palermo, Italy

[2] Vrije Univ Amsterdam, Amsterdam Univ, Canc Ctr Amsterdam, Dept Med Oncol,Med Ctr, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands

[3] Azienda Osped Univ Pisana, Unit Anat Pathol 2, Via Roma 67, I-56126 Pisa, Italy

[4] Vrije Univ Amsterdam, Fac Sci, Dept Chem & Pharmaceut Sci, AIMMS Div Mol Toxicol, De Boelelaan 1108, NL-1081 HZ Amsterdam, Netherlands

[5] Fdn Pisana Sci, Via Ferruccio Giovannini 13, I-56017 Pisa, Italy

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2020年 / 189卷

关键词：

Imidazo[2,1-b][1,3,4]thiadiazole derivatives; Pancreatic ductal adenocarcinoma; Antiproliferative activity; Inhibition of migration; Spheroids shrinkage; Modulation of EMT; PTK2/FAK; EPITHELIAL-MESENCHYMAL TRANSITIONS; TRANSCRIPTION FACTOR SNAIL; E-CADHERIN; NORTOPSENTIN ANALOGS; ANTITUMOR-ACTIVITY; RING-SYSTEMS; DESIGN; MECHANISMS; FAK; DERIVATIVES;

D O I：

10.1016/j.ejmech.2020.112088

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 mu M, and 0.29-12.2 mu M, 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. (C) 2020 Elsevier Masson SAS. All rights reserved.

引用

页数：18

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