Perifosine treatment exhibits a complex molecular response including the inhibition of Akt or the induction of apoptosis via clustering of death receptors in lipid rafts. However, the molecular response can vary between different tumor entities and the contribution of each target pathway to the activity of Perifosine might be distinct depending on the tumor entity or the agent combined with Perifosine. In this review we discuss the current view on the mechanism of action of perifosine in cancer and the contribution of the molecular targets of Perifosine to its activity.
As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7-aryl-1,5-naphthyridin-4-yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5-Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1-cyclopropyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]urea (49), displayed IC₅₀ values of 13 and 107 nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer-related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents.
A Convenient Synthesis of Novel 2,8-Disubstituted Pyrido[3,4-b]pyrazines Possessing Biological Activity. -Condensation of suitable diaminopyridines [cf. (III)] with α-ketoaldehyde derivatives results in a regioselective synthesis of pyrido[3,4-b]pyrazines (IV). The 8-bromo substituent is utilized for the introduction of a variety of N-substituents including, amino, anilines, amides, and ureas. -(ANTOINE, M.; GERLACH, M.; GUENTHER, E.; SCHUSTER, T.; CZECH, M.; SEIPELT, I.; MARCHAND*, P.; Synthesis 2012, 1, 69-82, http://dx.doi.org/10.1055/s-0031-1289613 ; Lab. Chim. Ther., Fac. Pharm., CNRS, Univ. Nantes, F-44035 Nantes, Fr.; Eng.) -Mais 17-180
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