Abstract
With the aim of discovering new anticancer agents, we have designed and synthesized novel α-aminophosphonate derivatives containing a 2-oxoquinoline structure using a convenient one-pot three-component method. The newly synthesized compounds were evaluated for antitumor activities against the A549 (human lung adenocarcinoma cell), HeLa (human cervical carcinoma cell), MCF-7 (human breast cancer cell), and U2OS (human osteosarcoma cell) cancer cell lines in vitro, employing a standard 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. The results of pharmacological screening indicated that many compounds exhibited moderate to high levels of antitumor activities against the tested cancer cell lines and that most compounds showed more potent inhibitory activities comparable to 5-fluorouracil (5-FU) which was used as a positive control. The mechanism of representative compound 4u (diethyl((2-oxo-1,2-dihydroquinolin-3-yl)(phenyl-amino)methyl)phosphonate) indicated that the compound mainly arrested HeLa cells in S and G2 stages and was accompanied by apoptosis in HeLa cells. This action was confirmed by acridine orange/ethidium bromide staining, Hoechst 33342 staining, and flow cytometry.
Highlights
Malignant cancer is the primary cause of human death worldwide [1], accounting for 8.2 million deaths in 2012, and it is expected that annual cases will rise from 14 million in 2012 to 22 within the two decades [2,3]
The in vitro cytotoxic potency of 2-oxo-quinoline aminophosphonate derivatives 4a–x were evaluated by MTT assay against A549, HeLa, MCF-7 and U2OS cancer cell lines with 5-fluorouracil (5-FU) as the positive control
A convenient one-pot three component reaction has been developed for the synthesis of 2-oxoquinoline α-aminophosphonate derivatives employing 2-oxoquinoline, aromatic amine, and diethyl phosphate
Summary
Malignant cancer is the primary cause of human death worldwide [1], accounting for 8.2 million deaths in 2012, and it is expected that annual cases will rise from 14 million in 2012 to 22 within the two decades [2,3]. During the last few decades, researchers have struggled to find effective clinical approaches for the treatment of cancer and have searched for novel anticancer agents, but the management of malignancies in humans still constitutes a major concern for contemporary medicine [4,5,6,7]. 2-Oxoquinolines (1, Scheme 1), a class of heterocyclic molecular scaffold, received much interest and attention due to their diverse pharmacological activities, which include antimicrobial [8], anti-angiogenic [9], anticancer [10], antioxidant [11], antimalarial [12], and anti-inflammatory [13,14] properties. Our present work is to design and synthesize α-aminophosphonates derivatives containing a 2-oxoquinoline skeleton, and investigate their potential anticancer activity against four human cancer cell lines. Preliminary research on the mode of action of representative compound 4u is investigated
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