Chalcone Derivatives: Role in Anticancer Therapy

biomolecules Review Chalcone Derivatives: Role in Anticancer Therapy Yang Ouyang 1,† , Juanjuan Li 1,†, Xinyue Chen 1, Xiaoyu Fu 1, Si Sun 2,* and Qi Wu 1,* 1 Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, China; [email protected] (Y.O.); [email protected] (J.L.); [email protected] (X.C.); [email protected] (X.F.) 2 Department of Clinical Laboratory, Renmin Hospital of Wuhan University, Wuhan 430060, China * Correspondence: [email protected] (S.S.); [email protected] (Q.W.); Tel.: +86-15827099866 (S.S.); +86-13296588817 (Q.W.) † These authors contributed equally to this work. Abstract: Chalcones (1,3-diaryl-2-propen-1-ones) are precursors for flavonoids and isoflavonoids, which are common simple chemical scaffolds found in many naturally occurring compounds. Many chalcone derivatives were also prepared due to their convenient synthesis. Chalcones as weandhetic analogues have attracted much interest due to their broad biological activities with clinical potentials against various diseases, particularly for antitumor activity. The chalcone family has demonstrated potential in vitro and in vivo activity against cancers via multiple mechanisms, including cell cycle disruption, autophagy regulation, apoptosis induction, and immunomodulatory and inflammatory mediators. It represents a promising strategy to develop chalcones as novel anticancer agents. In addition, the combination of chalcones and other therapies is expected to be an effective way to improve anticancer therapeutic efficacy. However, despite the encouraging results for their response to cancers observed in clinical studies, a full description of toxicity is required for their clinical use as safe drugs for the treatment of cancer. In this review, we will summarize the recent advances of the chalcone family as potential anticancer agents and the mechanisms of action. Besides, future Citation: Ouyang, Y.; Li, J.; Chen, X.; applications and scope of the chalcone family toward the treatment and prevention of cancer are Fu, X.; Sun, S.; Wu, Q. Chalcone brought out. Derivatives: Role in Anticancer Therapy. Biomolecules 2021, 11, 894. Keywords: chalcone; anticancer; molecular targets; bioactive dietary compounds https://doi.org/10.3390/ biom11060894 Academic Editor: Loredana Salerno 1. Introduction Cancer is caused by the uncontrolled growth of cells and is a multifactorial disease Received: 29 April 2021 that claims millions of lives each year worldwide. Its genesis and progression are extremely Accepted: 9 June 2021 Published: 16 June 2021 complex. A variety of strategies are applied to anticancer treatments, including surgery, chemotherapy, and radiotherapy used alone or in combination. However, multidrug resis- Publisher’s Note: MDPI stays neutral tance (MDR) and side effects constitute major impediments to effective cancer therapy [1]. with regard to jurisdictional claims in Phytochemicals, such as chalcones, have been shown to be inexpensive, readily available published maps and institutional affil- and relatively nontoxic. Certain chalcones can target key molecular reactions that may iations. induce the genesis and progression of cancer [2]. Thus, scientists are using traditional knowledge of medicinal plants and the sustainable exploitation of marine natural products to synthesize new, more powerful and effective therapeutic antitumor drugs by leveraging different molecular mechanisms [3–5]. A chalcone is a simple chemical scaffold in many natural plant products, including Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. spices, vegetables, fruits, teas [6–9]. Chalcones, which belong to the flavonoid family and This article is an open access article act as intermediates in the biosynthesis of flavonoids, exhibit structural heterogeneity and distributed under the terms and can act on various drug targets. Chalcone family members have received considerable conditions of the Creative Commons attention not only because of the possibilities for their synthetic and biosynthetic produc- Attribution (CC BY) license (https:// tion but also because of the scope of their biological activities, including anticancer [10], creativecommons.org/licenses/by/ anti-inflammatory [11], antidiabetic [12], cancer chemopreventive [13], antioxidant [14], 4.0/). antimicrobial [15], antileishmanial [16] and antimalarial activities [17]. More importantly, Biomolecules 2021, 11, 894. https://doi.org/10.3390/biom11060894 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 10, x 2 of 38 Biomolecules 2021, 11, 894 2 of 36 antimicrobial [15], antileishmanial [16] and antimalarial activities [17]. More importantly, severalseveral chalconechalcone compounds have have been been approv approveded for for market market and and clinical clinical use use for for various var- ioushealth health conditions conditions [e.g., [e.g.,as me astochalcone-choleretic/diuretics metochalcone-choleretic/diuretics (1); sofalcone-based (1); sofalcone-based anti-ul- anti-ulcer/mucoprotectivescer/mucoprotectives (2); and (2 );hesperidin and hesperidin methylchalcone-vascular methylchalcone-vascular protectives protectives (3)], exem- (3)], exemplifyingplifying the clinical the clinical potential potential of chalcones of chalcones [2,8,9,18] [2,8,9 (Figure,18] (Figure 1). 1). FigureFigure 1. 1.Chemical Chemical structures structures of of approved approved and and clinically clinically tested tested chalcones. chalcones. ChalconeChalcone compoundscompounds havehave aa chemical chemical scaffold scaffold of of 1,3-diaryl-2-propen-1-one, 1,3-diaryl-2-propen-1-one, which which cancan be be conveniently conveniently modified modified to to alter alter the the biological biological activities activities of theseof these molecules. molecules. By addingBy add- variousing various functional functional groups groups (aryls, (aryls, halogens, halogens hydroxyls,, hydroxyls, carboxyls, carboxyls, phenyl, phenyl, etc.) [18 etc.)], which [18], enablewhich chalconeenable chalcone binding binding with different with different molecular molecular targets and, targets as compounds, and, as compounds, interaction in- withteraction other with molecules, other molecules, chalcones exhibitchalcones a broad exhibit spectrum a broad of spectrum biological of activities. biological Therefore, activities. chalconesTherefore, are chalcones useful templates are useful for templates the development for the development of novel anticancer of novel agents. anticancer Moreover, agents. hybridizationMoreover, hybridization of the chalcone of the moiety chalcone with moiety other anticancerwith other pharmacophoresanticancer pharmacophores produces hybridsproduces that hybrids have that the potentialhave the potential to overcome to overcome drug resistance drug resistance and improve and improve therapeutic ther- specificity,apeutic specificity, rendering rendering it a promising it a strategy promising for developingstrategy for novel developing anticancer novel agents. anticancer In this review,agents. weIn this focus review, on the we medicinal focus on chemistrythe medicinal strategies chemistry employed strategies for employed the design for and the developmentdesign and development of anticancer of chalcones. anticancer Thechalcones. multiple The mechanisms multiple mechanisms of anticancer of anticancer activities exhibitedactivities byexhibited chalcones by and chalcones their therapeutic and their potentialtherapeutic are alsopotential summarized are also herein. summarized herein. 2. Strategies Employed to Produce Anticancer Chalcones 2. StrategiesChalcone Employed compounds to haveProduce a chemical Anticancer scaffold Chalcones of 1,3-diaryl-2-propen-1-one in trans- (4) or cis- (5) isomers with two aromatic rings (rings A and B) that are joined by a three- Chalcone compounds have a chemical scaffold of 1,3-diaryl-2-propen-1-one in trans- carbon unsaturated α,β-carbonyl system (Figure2). In most cases, the trans isomer is (4) or cis- (5) isomers with two aromatic rings (rings A and B) that are joined by a three- thermodynamically more stable, and therefore, it is the predominant configuration among carbon unsaturated α,β-carbonyl system (Figure 2). In most cases, the trans isomer is ther- chalcones [19]. In addition, chalcones contain many replaceable hydrogens, which enables modynamically more stable, and therefore, it is the predominant configuration among the use of various methods and schemes for the synthesis of chalcone derivatives [20]. chalcones [19]. In addition, chalcones contain many replaceable hydrogens, which enables In each of these methods, the most important part is the condensation of two aromatic the use of various methods and schemes for the synthesis of chalcone derivatives [20]. In systems (with nucleophilic and electrophilic groups) to yield the chalcone scaffold. The re- each of these methods, the most important part is the condensation of two aromatic sys- action scheme used in the synthesis of the standard scaffold of chalcones (1,3-diphenyl- tems (with nucleophilic and electrophilic groups) to yield the chalcone scaffold. The reac- 2-propen-1-one) includes Claisen–Schmidt condensation, carbonylative Heck coupling reaction,tion scheme coupling used reaction,in the synthesis Sonogashira of the isomerization standard scaffold coupling of chalcones reaction, continuous-flow (1,3-diphenyl-2- deuteractionpropen-1-one) reaction, includes Suzuki–Miyaura Claisen–Schmidt coupling condensation, reaction, one-potcarbonylative synthesis

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