Research Progress in the Modification of Quercetin Leading to Anticancer Agents

Abstract

The flavonoid quercetin (3,3',4',5,7-pentahydroxyflavone) is widely distributed in plants, foods, and beverages. This polyphenol compound exhibits varied biological actions such as antioxidant, radical-scavenging, anti-inflammatory, antibacterial, antiviral, gastroprotective, immune-modulator, and finds also application in the treatment of obesity, cardiovascular diseases and diabetes. Besides, quercetin can prevent neurological disorders and exerts protection against mitochondrial damages. Various in vitro studies have assessed the anticancer effects of quercetin, although there are no conclusive data regarding its mode of action. However, low bioavailability, poor aqueous solubility as well as rapid body clearance, fast metabolism and enzymatic degradation hamper the use of quercetin as therapeutic agent, so intense research efforts have been focused on the modification of the quercetin scaffold to obtain analogs with potentially improved properties for clinical applications. This review gives an overview of the developments in the synthesis and anticancer-related activities of quercetin derivatives reported from 2012 to 2016.

Keywords: anticancer; cell proliferation; cytotoxicity; methoxyflavones; multi-drug resistance (MDR); quercetin; quercetin derivatives.

Figure 1

Structure of quercetin and representation of flavone and flavonol backbones.

Figure 2

Structures of quercetin derivatives 1–7 along with their occurrence in food and plants.

Figure 3

General methodologies towards modified forms of quercetin.

Figure 4

Structures of O-methylated quercetin derivatives (4), (5), and (8–20).

Figure 5

Structures of O-alkylated quercetin derivatives (21–50). Abbreviations: Et: ethyl, Pr: propyl, Bu: butyl, Pe: pentyl, H_x: hexyl, i-Pr: isopropyl, i-Pe: isopentyl, Bn: benzyl.

Figure 5

Structures of O-alkylated quercetin derivatives (21–50). Abbreviations: Et: ethyl, Pr: propyl, Bu: butyl, Pe: pentyl, H_x: hexyl, i-Pr: isopropyl, i-Pe: isopentyl, Bn: benzyl.

Figure 6

Structures of quercetin derivatives 51–54 obtained by manipulation of C-4 carbonyl moiety.

Figure 7

Structure of quercetin derivative 55 obtained via replacement of catecholic hydroxyl groups.

Figure 8

Structures of O-acylated quercetin derivatives 56–63.

Figure 9

A- and B-ring functionalized quercetin derivatives 64–71.

Figure 10

Possible coordination modes of quercetin with metal ions (M).

Figure 11

Structures of quercetin-metal complexes 72–77.

Figure 12

Structure modifications of quercetin leading to the most promising anticancer analogs.