Design, synthesis, biological evaluation and molecular modeling study of new thieno[2,3-d]pyrimidines with anti-proliferative activity on pancreatic cancer cell lines.

Abstract

Pancreatic cancer is one of the most challenging diseases with seven months only as median survival time due to its poor prognosis. Several enzymes are blamed for the progress of pancreatic cancer especially, platelet-derived growth factor receptors (PDGFRs), this in turn makes them promising targets for its treatment. In this study, twenty eight new compounds based on thieno[2,3-d]pyrimidine scaffold were synthesized as anti-pancreatic cancer agents mimicking the benzofuro[3,2-d]pyrimidine derivative, amuvatinib. Various linkers including amides, esters, ketones, urea and thiourea derivatives were utilized to study their effect on the anti-proliferative activity of these compounds. Most of the tested compounds revealed good cytotoxic activities against pancreatic carcinoma cell line PANC-1. Compound 9d showed the highest cytotoxicity with an IC50 value of 5.4 µM. Furthermore, 9d showed excellent platelet derived growth factor receptor (PDGFR-α) inhibitory activity, with IC50 value 0.155 µM. Docking study was carried out into PDGFR-α active site which showed comparable binding mode to that of FDA approved PDGFR-α inhibitor, imatinib. 3D-Quantitative structure activity relationship (QSAR) model was built up with five-featured pharmacophore which could be implemented for emerging effective lead structures. These compounds could serve as a new chemotype for discovering new agents for pancreatic cancer therapy.

• Authors: Mohamed S H Salem, Yasmine M Abdel Aziz, Mohamed S Elgawish, Mohamed M Said, Khaled A M Abouzid
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 94 Pg. 103472 (01 2020) ISSN: 1090-2120 [Electronic] United States
• PMID: 31813475 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Pyrimidines
• thieno(2,3-d)pyrimidine
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Drug Design
• Drug Screening Assays, Antitumor
• Humans
• Models, Molecular
• Molecular Structure
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Pyrimidines (chemical synthesis, chemistry, pharmacology)
• Receptor, Platelet-Derived Growth Factor alpha (antagonists & inhibitors, metabolism)
• Structure-Activity Relationship