Synthesis of <i>Ortho</i>/<i>Ortho</i>′‑Substituted 1,1-Diarylethylenes through Cross-Coupling Reactions of Sterically Encumbered Hydrazones and Aryl Halides

The reactivity of sterically hindered <i>N</i>-tosylhydrazones <b>2</b> featuring <i>ortho</i>/<i>ortho</i>′-substituents on the aromatic ring with various <i>ortho</i>-, <i>meta</i>-, and <i>para</i>-substituted aryl halides <b>3</b> was investigated. To accomplish successfully this challenging coupling, fine-tuning of the reaction conditions were required. The newly established PdCl₂(MeCN)₂/Xphos/NaO-<i>t</i>-Bu/F-benzene system in a sealed tube is compatible with a broad spectrum of both coupling partners, regardless of their electronic and steric nature. This protocol has been applied successfully to the synthesis of a xanthene derivative

Csp²–N Bond Formation via Ligand-Free Pd-Catalyzed Oxidative Coupling Reaction of <i>N</i>‑Tosylhydrazones and Indole Derivatives

In a fresh approach to the synthesis of <i>N</i>-vinylazoles, a ligand-free palladium catalytic system was found to promote the Csp²–N bond-forming reaction utilizing <i>N</i>-tosylhydrazones and N-H azoles. This process shows functional group tolerance; di-, tri-, and tetrasubstituted <i>N</i>-vinylazoles were obtained in high yields. Under the optimized conditions, the reaction proceeds with high stereoselectivity depending on the nature of the coupling partners

Selective Metal-Free Deoxygenation of Unsymmetrical 1,2-Dicarbonyl Compounds by Chlorotrimethylsilane and Sodium Iodide

For the first time, the combination of chlorotrimethylsilane with NaI is used as a selective reducting system toward 1,2-diketones. This combination is successfully evaluated with several unsymmetrically benzil derivatives, which are reduced in good yields and with a total α-regioselectivity at room temperature. Identification of benzoin intermediates is achieved, and a mechanistic radical process is proposed

Therapeutic Modalities of Squalenoyl Nanocomposites in Colon Cancer: An Ongoing Search for Improved Efficacy

Drug delivery of combined cytotoxic and antivascular chemotherapies in multidrug nanoassemblies may represent an attractive way to improve the treatment of experimental cancers. Here we made the proof of concept of this approach on the experimental LS174-T human colon carcinoma xenograft nude mice model. Briefly, we have nanoprecipitated the anticancer compound gemcitabine conjugated with squalene (SQ-gem) together with isocombretastatin A-4 (isoCA-4), a new isomer of the antivascular combretastatin A-4 (CA-4). It was found that these molecules spontaneously self-assembled as stable nanoparticles (SQ-gem/isoCA-4 NAs) of <i>ca</i>. 142 nm in a surfactant-free aqueous solution. Cell culture viability tests and apoptosis assays showed that SQ-gem/isoCA-4 NAs displayed comparable antiproliferative and cytotoxic effects than those of the native gemcitabine or the mixtures of free gemcitabine with isoCA-4. Surprisingly, it was observed by confocal microscopy that the nanocomposites made of SQ-gem/isoCA-4 distributed intracellularly as intact nanoparticles whereas the SQ-gem nanoparticles remained localized onto the cell membrane. When used to deliver these combined chemotherapeutics to human colon cancer model, SQ-gem/isoCA-4 nanocomposites induced complete tumor regression (by 93%) and were found superior to all the other treatments, whereas the overall tolerance was better than the free drug treatments. This approach could be applied to other pairs of squalenoylated nanoassemblies with other non-water-soluble drugs, thus broadening the application of the “squalenoylation” concept in oncology

1,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin-Polymerization Inhibitors: Synthesis, Metabolism, and Biological Evaluation

We report the synthesis and metabolic and biological evaluation of a series of 17 novel heterocyclic derivatives of isocombretastatin-A4 (iso-CA-4) and their structure–activity relationships. Among these derivatives, the most active compound, <b>4f</b>, inhibited the growth of a panel of seven cancer cell lines with an IC₅₀ in the low nanomolar range. In addition, <b>4f</b> showed interesting activity against CA-4-resistant colon-carcinoma cells and multidrug-resistant leukemia cells. It also induced G₂/M cell-cycle arrest. Structural data indicated binding of <b>4f</b> to the colchicine site of tubulin, likely preventing the curved-to-straight tubulin structural changes that occur during microtubule assembly. Also, <b>4f</b> disrupted the blood-vessel-like assembly formed by human umbilical-vein endothelial cells in vitro, suggesting its function as a vascular-disrupting agent. An in vitro metabolism study of <b>4f</b> showed its high human-microsomal stability in comparison with that of iso-CA-4. The physicochemical properties of <b>4f</b> may be conducive to CNS permeability, suggesting that this compound may be a possible candidate for the treatment of glioblastoma