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
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.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Furans/pharmacology , Indoles/pharmacology , Tubulin Modulators/pharmacology , Tubulin/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Furans/chemical synthesis , Furans/chemistry , Humans , Indoles/chemistry , Molecular Structure , Polymerization/drug effects , Structure-Activity Relationship , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistryABSTRACT
Analogs containing a central 3-pyrrolin-2-one core with different methoxyphenyl and/or indole substituents were prepared and tested for anti-proliferative activity in U-937 cells. The most efficacious analogs were non-rigid, (non-fused) contained methoxyaryl groups located at the 4-position, and contained either methoxyaryl or indole groups located at the 3-position. Both the number of methoxy groups contained in the substituents and the particular location of the indole rings with respect to the lactam carbonyl had significant affects on anti-proliferative activity. This work provides a framework to better understand structure-activity relationships for inducing anti-proliferative activity in diaryl heterocyclic scaffolds.
Subject(s)
Antineoplastic Agents/pharmacology , Pyrrolidinones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cyclization , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Pyrrolidinones/chemical synthesis , Pyrrolidinones/chemistry , Structure-Activity RelationshipABSTRACT
A simple and flexible approach to 3-pyrrolin-2-one fused carbazoles is disclosed. The key step involves the BF3-mediated electrophilic substitution of indoles with N-alkyl-substituted 3-aryltetramic acids, which provides access to indole-substituted 3-pyrrolin-2-ones. Scholl-type oxidative cyclizations of these materials led to the formation of the corresponding 3-pyrrolin-2-one-fused benzo[a]carbazoles and indolo[2,3-a]carbazoles. This work represents the first synthesis of the benzo[a]pyrrolo[3,4-c]carbazol-3(8H)-one ring system, while the indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-one ring system is found in a number of biologically active compounds including the protein kinase C (PKC) inhibitor, staurosporine.
