(E)-2-Benzylidenecyclanones: Part XVIII Study the Possible Link between Glutathione Reactivity and Cancer Cell Cytotoxic Effects of Some Cyclic Chalcone Analogs A Comparison of the Reactivity of the Open-Chain and the Seven-Membered Homologs

Abstract

Non-enzymatic thiol addition into the α,β-unsaturated carbonyl system is associated with several biological effects. In vivo, the reactions can form small-molecule thiol (e.g., glutathione) or protein thiol adducts. The reaction of two synthetic (4′-methyl- and 4′-methoxy substituted) cyclic chalcone analogs with reduced glutathione (GSH) and N-acetylcysteine (NAC) was studied by (high-pressure liquid chromatography-ultraviolet spectroscopy) HPLC-UV method. The selected compounds displayed in vitro cancer cell cytotoxicity (IC50) of different orders of magnitude. The structure of the formed adducts was confirmed by (high-pressure liquid chromatography-mass spectrometry) HPLC-MS. The incubations were performed under three different pH conditions (pH 3.2/3.7, 6.3/6.8, and 8.0/7.4). The chalcones intrinsically reacted with both thiols under all incubation conditions. The initial rates and compositions of the final mixtures depended on the substitution and the pH. The frontier molecular orbitals and the Fukui function were carried out to investigate the effects on open-chain and seven-membered cyclic analogs. Furthermore, machine learning protocols were used to provide more insights into physicochemical properties and to support the different thiol-reactivity. HPLC analysis indicated diastereoselectivity of the reactions. The observed reactivities do not directly relate to the different in vitro cancer cell cytotoxicity of the compounds.

Synthesis of structural analogues of Reversan by ester aminolysis: an access to pyrazolo[1,5-a]pyrimidines from chalcones

“…2). 11,45,46 This attack is probably favored by fluoride ions (F − ) in the catalyst, having a verified ability to remove the hydrogen atom from NH -azoles; 43 likewise, the enone increases its electrophilicity when the carbonyl group interacts with alumina. Then, the cyclcondensation of I with the loss of a water molecule occurs to afford the dihydro derivative II (NH 2 /hard → CO/hard), which is oxidized to the product 4a–h with K 2 S 2 O 8 (1 equiv.)…”

(E)-2-Benzylidenecyclohexanones: Part XIX. Reaction Of (E)-2-(4′-X-benzylidene)-1-Tetralones with Cellular Thiols. Comparison of Thiol Reactivities of Open-Chain Chalcones and Their Six- and Seven-Membered Cyclic Analogs [1]

“…The electronic structures of 2a, CH3SH and CH3S -were studied using computational methods. The data, together with those previously published for 1a and 3a [26] are summarized in Table 4. The analysis revealed that the energies of the highest occupied molecular orbital (EHOMO) and the lowest unoccupied molecular orbital (ELUMO) are crucial for understanding the electron-donating and accepting capabilities of the molecules, respectively.…”

“…It was found, that both open-chain chalcones (1b and 1c) showed high and comparable reactivity under each condition [25]. On the contrary, between the cyclic analogs, the less cytotoxic methyl substituted 3b showed the higher reactivity [26]. In the comparison of the cytotoxicities of respective six-(2b and 2c) and sevenmembered (3b and 3c) derivatives, a reduction in cytotoxicities was observed in both pairs (Table 1).…”

“…Table 4. Reactivity indices were obtained for 1a [26] , 2a, 3a [26] , CH3SH [26] , and CH3S - [26] at the M06-2X/6-311++G(d,p) level of theory.…”

“…It was found that the relative position of the two aromatic rings, as well as the steric properties of the aromatic substituents, plays a determining role in the cytotoxicity of the compounds [22][23][24]. In our earlier works, reactivity the open-chain 1b, 1c, and their seven-membered cyclic analogs 3b and 3c with reduced glutathione (GSH) and N-acetylcysteine (NAC) was investigated under three conditions with different pH: (a) pH 8.0, (b) pH 6.3, and (c) pH 3.2 [25,26]. It was found, that both open-chain chalcones (1b and 1c) showed high and comparable reactivity under each condition [25].…”