ABSTRACT
Ko143, a potent ABCG2 inhibitor that reverses multidrug resistance in cancer, cannot be used clinically due to its unsuitable metabolic stability. We identified benzoyl indoles as reversal agents that reversed ABCG2-mediated multidrug resistance (MDR), with synthetic tractability and enhanced metabolic stability compared to Ko143. Bisbenzoyl indole 2 and monobenzoyl indole 8 significantly increased the accumulation of mitoxantrone (MX) in ABCG2-overexpressing NCI-H460/MX20â¯cells, and sensitized NCI-H460/MX20â¯cells to mitoxantrone. Mechanistic studies were conducted by [3H]-MX accumulation assay, Western blot analysis, immunofluorescence analysis and ABCG2 ATPase assay. The results revealed that the reversal efficacies of compounds 2 and 8 were not due to an alteration in the expression level or localization of ABCG2 in ABCG2-overexpressing cell lines. Instead, compounds 2 and 8 significantly stimulated the ATP hydrolysis of ABCG2 transporter, suggesting that these compounds could be competitive substrates of ABCG2 transporter. Overall, the results of our study indicated that compounds 2 and 8 significantly reversed ABCG2-mediated MDR by blocking the efflux of anticancer drugs.
Subject(s)
ATP Binding Cassette Transporter, Subfamily G, Member 2/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Diketopiperazines/pharmacology , Drug Resistance, Neoplasm/drug effects , Heterocyclic Compounds, 4 or More Rings/pharmacology , Neoplasm Proteins/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily G, Member 2/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Diketopiperazines/chemistry , Diketopiperazines/metabolism , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/metabolism , Humans , Molecular Structure , Neoplasm Proteins/metabolism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
A versatile Lewis acid catalyzed tandem cyclization of in situ generated alkynyl o-quinone methides ( o-AQMs) with electron-rich phenols has been developed on the basis of the mode involving an intermolecular 1,4-conjugate addition/6-endo cyclization/1,3-aryl shift/intramolecular 1,4-conjugate addition cascade. This reaction provides a new method for expeditious assembly of synthetically and biologically interesting tetracyclic bridged dioxabicyclo[3.3.1]nonane skeletons featuring a congested bridgehead oxa-quaternary stereocenter.
