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.
New series of analogues of N-(pyridin-4-yl)-2-[1-(4-chlorobenzyl)-indol-3-yl]glyoxamide D-24851 were synthesized, characterized and tested for their in vitro anticancer properties. In the first series, an amino acid spacer was introduced in the glyoxamide chain of D-24851. In the second series, the glyoxamide chain was moved to positions 4 and 5 of indole skeleton. These new compounds were tested on four cancer cell lines (KB, SK-OV-3, NCI-H460 and SF-268), with promising activity for the glycine derivative.
Preparation of Novel 2,3,8-Trisubstituted Pyrido[3,4-b]pyrazines and Pyrido[2,3-b]pyrazines. -An efficient synthetic approach to the preparation of the title compounds (VIII) and (XVI) is developed. -(ANTOINE, M.; CZECH, M.; GERLACH, M.; GUENTHER, E.; SCHUSTER, T.; MARCHAND*, P.; Synthesis 2011, 5, 794-806, http://dx.doi.org/10.1055/s-0030-1259429 ; Lab. Chim. Ther., Fac. Pharm., CNRS, Univ. Nantes, F-44035 Nantes, Fr.; Eng.) -C. Gebhardt 26-174
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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