Identification of potent cholecystokinin-B receptor antagonists: synthesis, molecular modeling and anti-cancer activity against pancreatic cancer cells

Abstract

Advanced malignant stages of pancreatic cancer have poor prognosis and very few treatment strategies are available. Pancreatic cancer is known to possess unique growth-related receptors that when activated, stimulate tumour proliferation. Gastrin and its related peptide cholecystokinin (CCK) are also significantly involved in the growth of this cancer type as well as other malignancies through activation of the cholecystokinin-B receptor (CCK-BR). New treatment strategies with CCK-BR antagonists are being suggested that suppress the growth promoting effects of gastrin. In this paper, we report the development of two series of quinazolinone derivatives incorporating hydrazinecarbothioamide (compounds ) and the hydrazino group (compounds) as linkers for developing CCK-BR antagonists. The affinities of the compounds were determined using docking into the CCK-BR homology modeled structure. The compounds were tested for CCK-BR binding and gastric acid secretion in an isolated lumen-perfused mouse stomach assay. The compounds exhibited CCK-BR binding activity (IC) in the range of 0.2-975 nM and showed good gastric acid secretion inhibitory activity. Molecular modeling of the compounds was done and pharmacophore mapping results showed good prediction of activity which correlated well with the experimental antagonistic activity. The compounds were further tested for their cytotoxicity on CCK-BR expressing pancreatic cancer cells. The results of the study provided two potent CCK-BR antagonists which also possess good to moderate growth inhibitory activities against pancreatic cancer cells.

Design and synthesis of novel quinazolinone-based derivatives as EGFR inhibitors with antitumor activity

“…Nineteen new quinazolin-4(3 H )-one derivatives 3a–g and 6a–l were synthesised according to Scheme 1 . The key starting compounds 3-phenyl-2-thioxo-2,3-dihydroquinazolin-4( 1H )-one ( 1a ) and 3–(4-chlorophenyl)-2-thioxo-2,3-dihydroquinazolin-4( 1H )-one ( 1b ) were obtained in good yields by reacting anthranilic acid with the appropriate aryl isothiocyanate in refluxing ethanol in presence of triethylamine as catalyst 30 , 31 . Compounds 1a,b were then treated with hydrazine hydrate 99% as reported to yield 2-hydrazinyl-3-phenylquinazolin-4( 3H )-one ( 2a ) and 3–(4-chlorophenyl)-2-hydrazinylquinazolin-4( 3H )-one ( 2b ) 31 .…”

“…The key starting compounds 3-phenyl-2-thioxo-2,3-dihydroquinazolin-4( 1H )-one ( 1a ) and 3–(4-chlorophenyl)-2-thioxo-2,3-dihydroquinazolin-4( 1H )-one ( 1b ) were obtained in good yields by reacting anthranilic acid with the appropriate aryl isothiocyanate in refluxing ethanol in presence of triethylamine as catalyst 30 , 31 . Compounds 1a,b were then treated with hydrazine hydrate 99% as reported to yield 2-hydrazinyl-3-phenylquinazolin-4( 3H )-one ( 2a ) and 3–(4-chlorophenyl)-2-hydrazinylquinazolin-4( 3H )-one ( 2b ) 31 . Furthermore, heating the obtained hydrazine derivatives 2a,b with 4-substituted benzaldehyde derivatives in ethanol as solvent in the presence of few drops of glacial acetic acid 42 afforded the novel target compounds 3a–g .…”

“…The original NMR spectra of the investigated compounds are provided as supporting information. Compounds 1a,b 30 , 31 , 2a,b 31 , 4a,b 32 , 33 and 5a,b 32 , 33 were prepared as reported.…”

Identification and Validation of the Hub Genes in Gastric Cancer Through Weighted Gene Co-Expression Network Analysis

“…Cholecystokinin is a well-known trophic factor for the gastrointestinal tract 56 , and CCKBR is correlated with pancreatic [56][57][58][59] , breast 60 , and gastric 61 cancers. Gastrin upregulates CCKBR in gastric cancer cell lines 62 , and thus it serves as a biomarker in gastric cancer treatment 63 .…”

Theoretical calculations of molecular descriptors for anticancer activities of 1, 2, 3-triazole-pyrimidine derivatives against gastric cancer cell line (MGC-803): DFT, QSAR and docking approaches

“…Owing to the enormous expenses or failure of most candidate drugs found in the market, their developments presently face liability such as possible side effects, in addition to their therapeutic properties. This makes the computational approach a hot topic and novel method due to its ability to speed up and assist drug design processes (Kumari et al, 2017). Therefore, this research aimed at calculating the molecular descriptors for anticancer activities of 1, 2, 3-triazole-pyrimidine hybrids using quantum chemical method and calculations of binding free energy via molecular docking.…”