Synthesis and Anticancer Cytotoxicity of Azaaurones Overcoming Multidrug Resistance

Abstract

The resistance of tumors against anticancer drugs is a major impediment for chemotherapy. Tumors often develop multidrug resistance as a result of the cellular efflux of chemotherapeutic agents by ABC transporters such as P-glycoprotein (ABCB1/P-gp), Multidrug Resistance Protein 1 (ABCC1/MRP1), or Breast Cancer Resistance Protein (ABCG2/BCRP). By screening a chemolibrary comprising 140 compounds, we identified a set of naturally occurring aurones inducing higher cytotoxicity against P-gp-overexpressing multidrug-resistant (MDR) cells versus sensitive (parental, non-P-gp-overexpressing) cells. Follow-up studies conducted with the P-gp inhibitor tariquidar indicated that the MDR-selective toxicity of azaaurones is not mediated by P-gp. Azaaurone analogs possessing pronounced effects were then designed and synthesized. The knowledge gained from structure-activity relationships will pave the way for the design of a new class of anticancer drugs selectively targeting multidrug-resistant cancer cells.

Bioactive Aurones, Indanones, and Other Hemiindigoid Scaffolds: Medicinal Chemistry and Photopharmacology Perspectives

“…By contrast, aurone derivatives were far less active, although they shared similar selectivity ratios. Higher IC 50 values of 60 μM and 15.0 μM were recorded for compound 17 , one of the best aurones in the series . Surely, more work is needed for improving the modest observed ratios and to further assess the true potential of the hemiindigoid family at targeting collateral sensitivity.…”

Stereoselective synthesis of 2-spirocyclopropyl-indolin-3-ones through cyclopropanation of aza-aurones with tosylhydrazones

“…(Z)-2-ylideneindolin-3-ones, namely aza-aurones, represent an interesting class of heterocyclic enones showing a broad range of applications in medicinal chemistry and in material sciences. Therefore, aza-aurones demonstrated potential applications as antimalarial, 1,2 antituberculotic 3 and anticancer agents 4 and, because of their peculiar photochemical behaviour, they have recently been studied as photoswitching systems. [5][6][7][8] However, aza-aurones are also known as powerful synthetic building blocks for cycloaddition reactions both as heterocyclic dienes, furnishing a "four-atom" unit, [9][10][11][12] or by reacting at the exocyclic double bond, providing an easy access to 3-oxo-2spiroannulated indolines (spiropseudoindoxyls) by [n+2] processes.…”

miR-199a: A Tumor Suppressor with Noncoding RNA Network and Therapeutic Candidate in Lung Cancer

“…The multidrug resistance (MDR) of tumors [ 76 ] was one of the leading causes of clinical chemotherapy failure, but the mechanism of drug resistance of tumors has yet to be fully elucidated. Currently, p-glycoprotein (P-GP), MDR-associated protein 1 (MRP1), and breast cancer drug resistance protein (BCRP) are recognized to be closely related to MDR [ 77 ]. In addition, studies have shown that extracellular vesicles (EVs) are involved in the communication between MDR cells and drug-sensitive cells, promoting the spread of the MDR phenotype.…”