The preparation of fluorescent nanoparticles containing squalenoyl-paclitaxel and a squalene-based fluorescein derivative is presented. The formation of self-assembled heteronanoparticles was confirmed by using the quasielastic light scattering (QELS) technique. The internalization in A549 human lung carcinoma cells was verified by microscopy analysis. Finally, paclitaxel in nanoassemblies maintains its ability to target microtubules.

The present study reports the preparation of a novel class of squalene conjugates with paclitaxel, podophyllotoxin, camptothecin and epothilone A. The obtained compounds are characterized by a squalene tail that makes them able to self-assemble in water, and by a drug unit connected via a disulfide-containing linker to secure the release inside the cell. All the obtained compounds were effectively able to self-assemble and to release the parent drug in vitro. Disulfide-containing paclitaxel squalene derivative showed a similar biological activity when compared to the free drug. Immunofluorescence assay shows that this squalene conjugate enters A549 cells and stain microtubule bundles. The results described herein pave the way for different classes of squalene-based releasable nanoassemblies. (C) 2014 Elsevier Masson SAS. All rights reserved.

Modern combinatorial chemistry is used to discover compounds with desired function by an alternative strategy, in which the biological target is directly involved in the choice of ligands assembled from a pool of smaller fragments. Herein, we present the first experimental result where the use of in situ click chemistry has been successfully applied to probe the ligand-binding site of Abl and the ability of this enzyme to form its inhibitor. Docking studies show that Abl is able to allow the in situ click chemistry between specific azide and alkyne fragments by binding to Abl-active sites. This report allows medicinal chemists to use protein-directed in situ click chemistry for exploring the conformational space of a ligand-binding pocket and the ability of the protein to guide its inhibitor. This approach can be a novel, valuable tool to guide drug design synthesis in the field of tyrosine kinases.

Invited for this month’s cover are the groups of Prof. Daniele Passarella, Prof. Graziella Cappelletti, Dr. Stephen Faulkner and Prof. John S. Snaith based at the Universities of Milano, Oxford and Birmingham. The image shows that a fluorescent tubulin binder could evidence the tubulin/microtubule network.

The introduction of a hydrophobic group at position 7 of 9-fluorenone-2-carboxylic acid generates new tubulin binders, the design of which is suggested by modeling studies. The synthesis is based on the use of 2,7-dibromo-fluorenone as starting material. The antiproliferative activity on two different cell lines, fluorescent microscopy, flow cytometry, and sedimentation assay tests confirmed the supposed mechanism.

The use of Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition permitted the synthesis of a new compound that is able to inhibit the HGF-induced scattering of MDCK (epithelial cells) and in vitro tumorigenesis of H1437 (non-small-cell lung cancer) and GTL-16 (human gastric carcinoma). In agreement with biochemical and biological results, docking studies within the ATP binding site of Met suggested for the new synthesized compound a binding mode similar to that of the active compound Triflorcas previously reported.

The introduction of a methylenthiol group at position 7 of camptothecin was carried out in four steps. This preparation also yielded the corresponding disulfide, which behaves as a prodrug due to its reactivity with glutathione. Assessment of their antiproliferative activities, investigations of their mechanism of action, and molecular modeling analysis indicated that the 7-modified camptothecin derivatives described herein maintain the biological activity and drug-target interactions of the parent compound.

The use of tubulin as a target to influence the composition of the mixture from a dynamic combinatorial library, based on the disulfide bond exchange reaction, is described. ESI-FT-ICR-MS was used to determine the composition of the library. The heterodimeric compound amplified by this approach was used to design the homologous derivative with a two-carbon spacer in place of the disulfide function. The ability of the compounds to inhibit tubulin polymerization is reported and compared to thiocolchicine.

N-[2-Methyl-5-(triazol-1-yl)phenyl]pyrimidin-2-amine derivatives were synthesized and evaluated in vitro for their potential use as inhibitors of Bcr-Abl. The design is based on the bioisosterism between the 1,2,3-triazole ring and the amide group. The synthesis involves a copper(I)-catalyzed azide-alkyne cycloaddi-tion (CuAAC) as the key step, with the exclusive production of anti-(1,4)-triazole derivatives. One of the compounds obtained shows general activity similar to that of imatinib; in particular, it was observed to be more effective in decreasing the fundamental function of cdc25A phosphatases in the K-562 cell line.

The preparation and biological evaluation of a novel series of dimeric camptothecin derivatives are described. All the new compounds showed a significant ability to inhibit human tumor cell growth with IC50 values ranging from 0.03 to 12.2 μM. The interference with the activity of the nuclear enzymes topoisomerases has been demonstrated, highlighting the poison effect of one of the obtained byproducts toward topoisomerase I. A moderate antiangiogenic activity has been demonstrated for one of the obtained compounds. Moreover, the effects of four new compounds on caspases activity and ROS generation have been studied on transgenic mouse cell.