10.1021/ml5000564
The research focuses on the discovery of new antimitotic compounds that modulate tubulin dynamics, addressing the limitations of existing cancer therapies like taxanes, which often face issues of resistance and toxicity. By employing phenotypic screening of a diverse compound library, the study identified a compound that induces mitotic arrest in human cells at submicromolar concentrations. The key chemical structures explored include biphenylacetamides, specifically a family termed biphenabulins, which were synthesized through simple methods involving amide and Suzuki couplings. The findings suggest that these compounds can effectively inhibit tubulin polymerization, with one compound showing potential allosteric inhibition at the colchicine-binding site, thus providing promising alternatives for further development in cancer treatment.
10.1021/jo051636h
The study focuses on the synthesis of colchicine, a naturally occurring compound with therapeutic properties, using a palladium-catalyzed siloxane cross-coupling methodology. The key chemicals involved in this approach include 5-bromotropolone, various aryl siloxane derivatives, and a palladium catalyst with a high degree of phosphine ligand coordination. These chemicals serve to form the aryl-tropolone bond, which is a critical step in the synthesis of colchicine. The study investigates and optimizes the coupling conditions for a range of highly functionalized aryl siloxane derivatives, aiming to develop an efficient method for constructing the carbocyclic framework of colchicine and its derivatives. The research also provides a direct comparison between siloxane and boronic acid coupling technologies, demonstrating their efficiency in producing highly functionalized biaryl products.
10.1039/c5ra01871d
The research aims to develop more potent and selective anti-lung cancer drugs based on the podophyllotoxin scaffold by introducing aryl dihydrothiazol moieties to improve water solubility and pharmacokinetic parameters. Seventeen aryl dihydrothiazol acyl podophyllotoxin ester derivatives (S1–S17) were synthesized and evaluated for their anticancer activities against three lung cancer cell lines (A549, Calu-1, 973) and two normal cell lines (Vero and L02) using the MTT assay. Among them, S12 exhibited the most potent anticancer effect against the A549 cell line with an IC50 value of 0.18 mM, while showing lower cytotoxicity against normal cells. Flow cytometry analysis revealed that S12 caused significant cell cycle arrest at the G2/M phase but had a moderate effect on apoptosis. Docking simulation results indicated that S12 could bind to the colchicine binding site of tubulin, and confocal microscopy and protein expression determination assays confirmed that S12 inhibited tubulin polymerization. The study concludes that S12 is a promising anti-cancer agent targeting tubulin polymerization.
10.1002/chem.200401294
This study investigated the use of glycopeptide dendrimers as drug delivery devices for colchicine, an antimitotic agent that inhibits cell division by binding to tubulin. The researchers designed peptide dendrimers with cysteine ??residues as the core for colchicine binding and functionalized the dendrimers with various glycosidic moieties such as β-glucose, α-galactose, α-N-acetylgalactose, and lactose on the surface to promote cellular uptake. The dendrimers were synthesized using solid-phase peptide synthesis and different glycosidic linkage strategies, including oxime bond formation, reductive alkylation, and amide bond formation. The bioactivity of the glycopeptide dendrimer conjugates was evaluated in HeLa tumor cells and non-transformed mouse embryonic fibroblasts (MEFs). The results showed that the glycopeptide dendrimer complexes inhibited HeLa cell proliferation 20-100 times more potently than the MEF complexes, indicating enhanced selectivity against cancer cells. This study demonstrates that glycopeptide dendrimers can serve as selective carriers to deliver cytotoxic compounds to cancer cells and have the potential to be further optimized to target specific cell types and deliver other drugs.
10.1071/CH9921577
The study investigates the synthesis, structural characterization, and tubulin-binding properties of two ketone derivatives of colchicine, namely 7-oxodeacetamidocolchicine (2) and 7-oxodeacetamidoisocolchicine (3). The researchers converted commercially available (-)-colchicine (1) into these ketones via deacetylcolchiceine (4) as an intermediate. The primary goal was to develop a reliable synthetic route for these compounds, which are of interest due to their potential for enantioselective reduction studies and their biological properties. The study also explores the X-ray crystal structures of compounds (2) and (3) to understand their molecular conformations and how they interact with tubulin. Additionally, the tubulin-binding properties of these ketones were evaluated to assess their potential as antitumor agents. The results showed that while compound (2) exhibited significant inhibitory effects on tubulin polymerization, compound (3) had little effect, highlighting the importance of molecular structure in biological activity.
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