1207534-99-3Relevant articles and documents
Molecular requirements for the expression of antiplatelet effects by synthetic structural optimized analogues of the anticancer drugs imatinib and nilotinib
Alivertis, Dimitrios,Brentas, Alexios,Ntemou, Nikoleta,Pantazi, Despoina,Skobridis, Konstantinos,Tselepis, Alexandros D.
, p. 4225 - 4238 (2019/12/25)
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.
Novel imatinib derivatives with altered specificity between Bcr-Abl and FMS, KIT, and PDGF receptors
Skobridis, Konstantinos,Kinigopoulou, Maria,Theodorou, Vassiliki,Giannousi, Emilia,Russell, Alison,Chauhan, Rakhee,Sala, Roberta,Brownlow, Nicola,Kiriakidis, Serafim,Domin, Jan,Tzakos, Andreas G.,Dibb, Nick J.
scheme or table, p. 130 - 139 (2010/11/02)
Imatinib is a clinically important ATP analogue inhibitor that targets the tyrosine kinase domain of the intracellular Abl kinase and the PDGF receptor family. Imatinib has revolutionised the treatment of chronic myeloid leukaemia, which is caused by the oncogene Bcr-Abl and certain solid tumours that harbor oncogenic mutations of the PDGF receptor family. As a leading kinase inhibitor, imatinib also provides an excellent model system to investigate how changes in drug design impact biological activity, which is an important consideration for rational drug design. Herein we report a new series of imatinib derivatives that in general have greater activity against the family of PDGF receptors and poorer activity against Abl, as a result of modifications of the phenyl and N-methylpiperazine rings. These new compounds provide a platform for further drug development against the therapeutically important PDGF receptor family and they also provide insight into the engineering of drugs with altered biological activity.
