1-Aryl-3-Ethyl-3-Methyl- and 1-Aryl-3-Methylsuccinimides as Drug Candidates for Cancer: Toxicity Prediction, Molecular Docking, and In Vitro Assessment

Abstract

Twenty-four succinimide derivatives were tested for their antiproliferative effect toward steroid hormone-responsive carcinoma cell lines: estrogen positive human breast carcinoma (MCF-7), lung carcinoma (A549), colon carcinoma (HT-29), and cervix carcinoma (HeLa). In addition, their antiproliferative effect was analyzed against late-stage estrogen and progesterone negative breast carcinoma (MDA-MB-231) and for safety were also investigated against normal fetal lung (MRC-5) cell lines. Molecular docking studies were conducted to observe their binding affinity for steroid hormone receptors and BCRP/ABCG2 transporter. All analyzed succinimides exhibited antiproliferative effects on at least one carcinoma cell line and were safe toward normal fetal lung cells. Their safety was confirmed based on in silico predictions. The succinimides were binding through the same π−stock interactions for the same Phe-778 of the progesterone receptor as the proven ligand and the same Phe-439 of the BCRP as the proven substrate and inhibitor. In addition, interactions with crucial amino acid residues for ligand antagonistic effects on estrogen receptors were observed. The QSAR analysis revealed that the succinimides' binding affinity for sex hormone receptors was governed by their flatness, polarity, size, and polarizability, while the affinity to bind for BCRP was lipophilicity dependent. The succinimides antiproliferative effect on A549 cell line given as IC₅₀ was statistically significant associated with their molar refractivity (p = 0.033), and lipophilicity (XlogP3, p = 0.043), respectively. Finally, the most promising drug candidate with the most pronounced anticancer activity was compound D11 against lung carcinoma (A549) cell lines with an IC₅₀ comparable to doxorubicin.