Identification of Flavone Derivative Displaying a 4′-Aminophenoxy Moiety as Potential Selective Anticancer Agent in NSCLC Tumor Cells

Abstract

Five heterocyclic derivatives were synthesized by functionalization of a flavone nucleus with an aminophenoxy moiety. Their cytotoxicity was investigated in vitro in two models of human non-small cell lung cancer (NSCLC) cells (A549 and NCI-H1975) by using MTT assay and the results compared to those obtained in healthy fibroblasts as a non-malignant cell model. One of the aminophenoxy flavone derivatives (APF-1) was found to be effective at low micromolar concentrations in both lung cancer cell lines with a higher selective index (SI). Flow cytometric analyses showed that APF-1 induced apoptosis and cell cycle arrest in the G2/M phase through the up-regulation of p21 expression. Therefore, the aminophenoxy flavone-based compounds may be promising cancer-selective agents and could serve as a base for further research into the design of flavone-based anticancer drugs.

Flavones and Related Compounds: Synthesis and Biological Activity

“…A series of new heterocyclic derivatives were recently synthesized via the functionalization of a flavone ring with an aminophenoxy moiety in different positions of the A ring and a phenoxy moiety in different positions of the B ring [ 34 ]. Their cytotoxicity was investigated in vitro against two human non-small cell lung cancer (NSCLC) cell lines (A549 and NCI-H1975).…”

“…A flavone derivative containing a phenoxy moiety at the C’3 position of the B ring and a p -aminophenoxy group at the sixth position of the A ring was the most effective, presenting micromolar IC 50 values (for A549 and H1975) and a high selectivity index (SI > 10, Table 1 , line 10). Further flow cytometric analyses showed that this compound induces apoptosis and cell cycle arrest in the G2/M phase through the up-regulation of p21 expression [ 34 ]. The absence of the phenoxy moiety on the B ring and the different position of the p -aminophenoxy moieties on the A ring decreased the efficacy and selectivity of aminophenoxy derivatives [ 34 ].…”

“…Further flow cytometric analyses showed that this compound induces apoptosis and cell cycle arrest in the G2/M phase through the up-regulation of p21 expression [ 34 ]. The absence of the phenoxy moiety on the B ring and the different position of the p -aminophenoxy moieties on the A ring decreased the efficacy and selectivity of aminophenoxy derivatives [ 34 ].…”

“…At present, the cyclization of o -hydroxychalcones using iodine in dimethyl sulfoxide still represents the principal method for the synthesis of flavones and their analogs with various structures. This method is still finding multiple applications because it generally allows for obtaining the target compounds with high yields, while the o -hydroxychalcones needed as precursors can be easily obtained via Claisen–Schmidt condensation [ 30 , 34 , 35 , 46 , 47 , 61 ].…”