Molecular Requirements for the Expression of Antiplatelet Effects by Synthetic Structural Optimized Analogues of the Anticancer Drugs Imatinib and Nilotinib

Abstract

Background

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 μΜ and 3.91 μΜ, 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

Acknowledgments

The authors thank the Atherothrombosis Research Center of the University of Ioannina for providing access to the laboratory equipment and facilities. We appreciate the use of NMR Unit and the Unit of Environmental, Organic and Biochemical high-resolution analysis – ORBITRAP-LC-MS of the University of Ioannina for providing access to the facilities funded by the Network of Research Supporting Laboratories of the University of Ioannina. This research has been financially supported by General Secretariat for Research and Technology (GSRT) and the Hellenic Foundation for Research and Innovation (HFRI) (Scholarship Codes: 2000 and 82195).

Supporting Materials

¹H NMR, ¹³C NMR and high-resolution ESI-MS spectra (Figures S1–12) of the nilotinib (V, VI) and imatinib/nilotinib (VII, VIII) analogues are provided as Supplementary materials.

Disclosure

The authors report no conflicts of interest in this work.