Drug Design, Development and Therapy (Dec 2019)
Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib
Abstract
Despoina Pantazi,1 Nikoleta Ntemou,2 Alexios Brentas,2 Dimitrios Alivertis,3 Konstantinos Skobridis,2 Alexandros D Tselepis1 1Department of Chemistry, Atherothrombosis Research Centre, Laboratory of Biochemistry, University of Ioannina, Ioannina 45110, Greece; 2Department of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, Ioannina 45110, Greece; 3Department of Biological Applications and Technology, University of Ioannina, Ioannina 45110, GreeceCorrespondence: Konstantinos SkobridisDepartment of Chemistry, Section of Organic Chemistry and Biochemistry, University of Ioannina, Ioannina 45110, GreeceTel + 30 26510 08598Fax + 30 26510 08682Email [email protected]: Platelets play important roles in cancer progression and metastasis, as well as in cancer-associated thrombosis (CAT). Tyrosine kinases are implicated in several intracellular signaling pathways involved in tumor biology, thus tyrosine kinase inhibitors (TKIs) represent an important class of anticancer drugs, based on the concept of targeted therapy.Purpose: The objective of this study is the design and synthesis of analogues of the TKIs imatinib and nilotinib in order to develop tyrosine kinase inhibitors, by investigating their molecular requirements, which would express antiplatelet properties.Methods: Based on a recently described by us improved approach in the preparation of imatinib and/or nilotinib analogues, we designed and synthesized in five-step reaction sequences, 8 analogues of imatinib (I–IV), nilotinib (V, VI) and imatinib/nilotinib (VII, VIII). Their inhibitory effects on platelet aggregation and P-selectin membrane expression induced by arachidonic acid (AA), adenosine diphosphate (ADP) and thrombin receptor activating peptide-6 (TRAP-6), in vitro, were studied. Molecular docking studies and calculations were also performed.Results: The novel analogues V–VIII were well established with the aid of spectroscopic methods. Imatinib and nilotinib inhibited AA-induced platelet aggregation, exhibiting IC50 values of 13.30 μ&Mgr; and 3.91 μ&Mgr;, respectively. Analogues I and II exhibited an improved inhibitory activity compared with imatinib. Among the nilotinib analogues, V exhibited a 9-fold higher activity than nilotinib. All compounds were less efficient in inhibiting platelet aggregation towards ADP and TRAP-6. Similar results were obtained for the membrane expression of P-selectin. Molecular docking studies showed that the improved antiplatelet activity of nilotinib analogue V is primarily attributed to the number and the strength of hydrogen bonds.Conclusion: Our results show that there is considerable potential to develop synthetic analogues of imatinib and nilotinib, as TKIs with antiplatelet properties and therefore being suitable to target cancer progression and metastasis, as well as CAT by inhibiting platelet activation.Keywords: cancer, kinase inhibitors, platelets, synthesis, thrombosis
