Synthesis of Novel Nilotinib Analogues and Biological Evaluation of Their Antiplatelet Activity and Functionality towards Cancer Cell Proliferation In Vitro.

Nilotinib, a second-generation tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia (CML), inhibits Bcr-Abl tyrosine kinase activity and proliferation of Bcr-Abl-expressing cells, as well as other malignancies. In the present study, new nilotinib analogues were synthesized and fully characterized. A platelet aggregation assay was performed, and the expression of P-selectin and PAC-1, as well as the effect on the proliferation of healthy endothelial cells, were evaluated.

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

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.

Two terphenyl-based diol hosts and corresponding solvent inclusions with dimethylformamide and acetonitrile.

Having reference to an elongated structural modification of 2,2'-bis(hydroxydiphenylmethyl)biphenyl, (I), the two 1,1':4',1''-terphenyl-based diol hosts 2,2''-bis(hydroxydiphenylmethyl)-1,1':4',1''-terphenyl, C44H34O2, (II), and 2,2''-bis[hydroxybis(4-methylphenyl)methyl]-1,1':4',1''-terphenyl, C48H42O2, (III), have been synthesized and studied with regard to their crystal structures involving different inclusions, i.e. (II) with dimethylformamide (DMF), C44H34O2·C2H6NO, denoted (IIa), (III) with DMF, C48H42O2·C2H6NO, denoted (IIIa), and (III) with acetonitrile, C48H42O2·CH3CN, denoted (IIIb).

Factor-inhibiting HIF-1 (FIH-1) is required for human vascular endothelial cell survival.

Factor-inhibiting hypoxia-inducible factor (HIF)-1 (FIH-1) is an asparaginyl β-hydroxylase enzyme that was initially found to hydroxylate the HIF-α, preventing its transcriptional activity and leading to adaptive responses to hypoxia. More recently, other substrates, such as neurogenic locus notch homolog (Notch), have been found to be alternative FIH targets, but the biologic relevance of this regulation was never investigated. Given the key function of Notch in angiogenesis, we here investigate the role of FIH/Notch signaling in endothelial cells.

Proteome Changes Induced by Imatinib and Novel Imatinib Derivatives in K562 Human Chronic Myeloid Leukemia Cells.

Imatinib mesylate is the leading compound to treat chronic myeloid leukemia (CML) and other cancers, through its inhibition of Bcr-Abl tyrosine kinases. However, resistance to imatinib develops frequently, particularly in late-stage disease and has necessitated the development of new Bcr-Abl inhibitors. The synthesis of a new series of phenylaminopyrimidines, structurally related to imatinib, showed large interest since the introduction of nilotinib.

Synthetic methodologies in organic chemistry involving incorporation of [¹⁷O] and [¹⁸O] isotopes.

This review is a critical survey of the literature that aims to highlight the most significant developments on synthetic strategies involving stable oxygen isotopes ([(17)O] and [(18)O]). The labeling methodologies are categorized in groups, according to the oxygen-containing functional group.

3,3''-Bis(9-hy-droxy-fluoren-9-yl)-1,1':3',1''-terphen-yl.

The asymmetric unit of the title compound, C44H30O2, contains two independent mol-ecules in which the terminal rings of the terphenyl element are inclined at angles of 36.3 (1) and 22.5 (1)° with respect to the central ring and the dihedral angles between the fluorenyl units are 72.

Novel imatinib derivatives with altered specificity between Bcr-Abl and FMS, KIT, and PDGF receptors.

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.