ABSTRACT
Due to the central role of tubulin in various cellular functions, it is a validated target for anti-cancer therapeutics. However, many of the current tubulin inhibitors are derived from complex natural products and suffer from multidrug resistance, low solubility, toxicity issues, and/or the lack of multi-cancer efficacy. As such, there is a continued need for the discovery and development of new anti-tubulin drugs to enter the pipeline. Herein we report on a group of indole-substituted furanones that were prepared and tested for anti-cancer activity. Molecular docking studies showed positive correlations between favorable binding in the colchicine binding site (CBS) of tubulin and anti-proliferative activity, and the most potent compound was found to inhibit tubulin polymerization. These compounds represent a promising new structural motif in the search for small heterocyclic CBS cancer inhibitors.
Subject(s)
Antineoplastic Agents , Tubulin , Tubulin/metabolism , Antineoplastic Agents/chemistry , Molecular Docking Simulation , Structure-Activity Relationship , Cell Proliferation , Cell Line, Tumor , Tubulin Modulators/chemistry , Colchicine/chemistry , Binding Sites , Indoles/chemistry , Drug Screening Assays, AntitumorABSTRACT
Glycolipid biosurfactants are of interest for various industry sectors. We report the synthesis and characterization of enantiopure poly-amido-saccharides (PASs) containing myristoyl (C14), palmitoyl (C16), or stearoyl (C18) terminal chain lengths as mimetics of glycolipid biosurfactants. These amphiphilic polymers are water soluble, adopt a helical secondary structure, decompose at temperatures greater than 240 °C, are non-cytotoxic, and self-assemble into nanostructures. Polymers containing the shorter hydrophilic chain lengths and the hydrophobic C14 chain exhibit the lowest surface tension among all polymers.
Subject(s)
Carbohydrates , Glycolipids , Carbohydrates/chemistry , Hydrophobic and Hydrophilic Interactions , Polymers/chemistry , Surface-Active Agents/chemistryABSTRACT
Analogs of diarylpyrrolinone lead compound 1 were prepared and tested for anti-proliferative activity in U-937 cancer cells. Alterations of 1 focused on modifying the two nitrogen atoms: a) the pyrrolinone nitrogen atom was substituted with a propyl group or replaced with an oxygen atom (furanone), and b) the substituents on the indole nitrogen were varied. These changes led to the discovery of a furanone analog 3b with sub-micromolar anti-cancer potency and tubulin polymerization inhibition activity.