Analogues of Natural Chalcones as Efficient Inhibitors of AKR1C3

Abstract

Naturally occurring substances are valuable resources for drug development. In this respect, chalcones are known to be antiproliferative agents against prostate cancer cell lines through various mechanisms or targets. Based on the literature and preliminary results, we aimed to study and optimise the efficiency of a series of chalcones to inhibit androgen-converting AKR1C3, known to promote prostate cancer. A total of 12 chalcones with different substitution patterns were synthesised. Structure–activity relationships associated with these modifications on AKR1C3 inhibition were analysed by performing enzymatic assays and docking simulations. In addition, the selectivity and cytotoxicity of the compounds were assessed. In enzymatic assays, C-6′ hydroxylated derivatives were more active than C-6′ methoxylated derivatives. In contrast, C-4 methylation increased activity over C-4 hydroxylation. Docking results supported these findings with the most active compounds fitting nicely in the binding site and exhibiting strong interactions with key amino acid residues. The most effective inhibitors were not cytotoxic for HEK293T cells and selective for 17β-hydroxysteroid dehydrogenases not primarily involved in steroid hormone metabolism. Nevertheless, they inhibited several enzymes of the steroid metabolism pathways. Favourable substitutions that enhanced AKR1C3 inhibition of chalcones were identified. This study paves the way to further develop compounds from this series or related flavonoids with improved inhibitory activity against AKR1C3.

Two Important Anticancer Mechanisms of Natural and Synthetic Chalcones

“…Data from literature indicate that molecules with a 1,3-diaryl-2-propen-1-one residue have numerous biological activities and, for this reason, are of particular pharmacological importance [ 92 , 93 ]. Among the most important biological activities of chalcones are antitumor, antibacterial, anti-inflammatory, antifungal, cytotoxic, antiviral, antimalarial, antituberculous, antiparasitic, antiulcer, analgesic, antipyretic, antihepatotoxic, etc., properties [ 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 ]. Chalcones have an extended conjugate system, which facilitates their binding to bioactive molecules, such as enzymes and DNA [ 121 ].…”

The Spectrum of Pharmacological Actions of Syringetin and Its Natural Derivatives—A Summary Review

“…Methylation also affords much better transport of the molecules through biological membranes, for example in the intestinal absorption, and considerably enhances oral bioavailability. Moreover, methylation of flavonoids provides the derivatives with increased biological activity, e.g., having the capability to inhibit cancer cell proliferation [ 10 ].…”

Hybrid Catalysts from Copper Biosorbing Bacterial Strains and Their Recycling for Catalytic Application in the Asymmetric Addition Reaction of B2(pin)2 on α,β-Unsaturated Chalcones

“…The possibility to introduce substituents with different electronic and steric properties on both the phenyl rings along with the presence the unsaturated Michael acceptor function make the chalcone skeleton a privileged scaffold in medicinal chemistry, able to interact with different thiol-containing biomolecules [22,23]. Many studies reported the use of chalcones as anticancer agents with novel targets and mechanisms of action [24]. Chalcones have indeed a poor probability to directly interact with DNA, thus reducing the risk of mutagenicity and leading to potential cytotoxic compounds with reduced sideeffects [25].…”