Authors: Isis A. Y. Ventura-Salazar | Francisco José Palacios‐Can | Leticia González‐Maya | Jessica Nayelli Sánchez‐Carranza | Mayra Antunez‐Mojica | Rodrigo Said Razo‐Hernández | Laura Álvarez
Source: Molecules (article, 2023-07-18)
Field: Chemistry — Organic Chemistry

Finding a Novel Chalcone–Cinnamic Acid Chimeric Compound with Antiproliferative Activity against MCF-7 Cell Line Using a Free-Wilson Type Approach In this work, we carried out the design and synthesis of new chimeric compounds from the natural cytotoxic chalcone 2',4'-dihydroxychalcone (2',4'-DHC, <b>A</b>) in combination with cinnamic acids. For this purpose, a descriptive and predictive quantitative structure-activity relationship (QSAR) model was developed to study the chimeric compounds' anti-cancer activities against human breast cancer MCF-7, relying on the presence or absence of structural motifs in the chalcone structure, like in a Free-Wilson approach. For this, we used 207 chalcone derivatives with a great variety of structural modifications over the α and β rings, such as halogens (F, Cl, and Br), heterocyclic rings (piperazine, piperidine, pyridine, etc.), and hydroxyl and methoxy groups. The multilinear equation was obtained by the genetic algorithm technique, using logIC<sub>50</sub> as a dependent variable and molecular descriptors (constitutional, topological, functional group count, atom-centered fragments, and molecular properties) as independent variables, with acceptable statistical parameter values (R2 = 86.93, Q2<i><sub>LMO</sub></i> = 82.578, Q2<i><sub>BOOT</sub></i> = 80.436, and Q2<i><sub>EXT</sub></i> = 80.226), which supports the predictive ability of the model. Considering the aromatic and planar nature of the chalcone and cinnamic acid cores, a structural-specific QSAR model was developed by incorporating geometrical descriptors into the previous general QSAR model, again, with acceptable parameters (R2 = 85.554, Q2<i><sub>LMO</sub></i> = 80.534, Q2<i><sub>BOOT</sub></i> = 78.186, and Q2<i><sub>EXT</sub></i> = 79.41). Employing this new QSAR model over the natural parent chalcone 2',4'-DHC (<b>A</b>) and the chimeric compound 2'-hydroxy,4'-cinnamate chalcone (<b>B</b>), the predicted cytotoxic activity was achieved with values of 55.95 and 17.86 µM, respectively. Therefore, to corroborate the predicted cytotoxic activity compounds <b>A</b> and <b>B</b> were synthesized by two- and three-step reactions. The structures were confirmed by <sup>1</sup>H and <sup>13</sup>C NMR and ESI+MS analysis and further evaluated in vitro against HepG2, Hep3B (liver), A-549 (lung), MCF-7 (breast), and CasKi (cervical) human cancer cell lines. The results showed IC<sub>50</sub> values of 11.89, 10.27, 56.75, 14.86, and 29.72 µM, respectively, for the chimeric cinnamate chalcone <b>B</b>. Finally, we employed <b>B</b> as a molecular scaffold for the generation of cinnamate candidates (<b>C</b>-<b>K</b>), which incorporated structural motifs that enhance the cytotoxic activity (pyridine ring, halogens, and methoxy groups) according to our QSAR model. ADME/tox in silico analysis showed that the synthesized compounds <b>A</b> and <b>B</b>, as well as the proposed chalcones <b>C</b> and <b>G</b>, are the best candidates with adequate drug-likeness properties. From all these results, we propose <b>B</b> (as a molecular scaffold) and our two QSAR models as reliable tools for the generation of anti-cancer compounds over the MCF-7 cell line. Chalcone ; Quantitative structure–activity relationship ; Chemistry ; Stereochemistry ; Cinnamic acid ; Applicability domain ; Aromaticity ; Organic chemistry ; Molecule Synthesis and biological activity ; Bioactive Compounds and Antitumor Agents ; Fungal Plant Pathogen Control