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1-Aryl-3-Ethyl-3-Methyl- and 1-Aryl-3-Methylsuccinimides as Drug Candidates for Cancer: Toxicity Prediction,
Damir Pinter1, Nataša Milošević1, Maja Milanović1
1Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia.
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.
Insights
Twenty-four succinimide derivatives show antiproliferative effects against various cancer cell lines, including lung carcinoma (A549), while remaining safe for normal cells. Compound D11 demonstrated significant potential as an anticancer drug candidate.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Computational Chemistry
Background:
- Development of novel anticancer agents is crucial for treating hormone-responsive and hormone-negative carcinomas.
- Succinimide derivatives represent a class of compounds with potential therapeutic applications.
- Understanding molecular interactions with steroid hormone receptors and transporters is key to drug design.
Purpose of the Study:
- To evaluate the antiproliferative activity of 24 succinimide derivatives against multiple human carcinoma cell lines.
- To assess the safety profile of these compounds against normal human lung fibroblasts.
- To investigate the molecular mechanisms of action using molecular docking and Quantitative Structure-Activity Relationship (QSAR) analyses.
Main Methods:
- In vitro antiproliferative assays on MCF-7, A549, HT-29, HeLa, and MDA-MB-231 cell lines.
- Cytotoxicity assessment on normal fetal lung MRC-5 cells.
- Molecular docking simulations targeting steroid hormone receptors and BCRP/ABCG2 transporter.
- QSAR analysis to correlate structural properties with binding affinity and antiproliferative activity.
Main Results:
- All tested succinimides demonstrated antiproliferative effects on at least one cancer cell line and were found safe for normal lung cells.
- Molecular docking revealed specific binding interactions with progesterone receptor (Phe-778) and BCRP transporter (Phe-439), similar to known ligands.
- Interactions with estrogen receptor residues critical for antagonistic effects were observed; QSAR indicated flatness, polarity, size, and polarizability influence sex hormone receptor binding, while lipophilicity affects BCRP binding.
- Compound D11 exhibited potent antiproliferative activity against A549 lung carcinoma cells, with an IC50 value comparable to doxorubicin.
Conclusions:
- Succinimide derivatives possess significant antiproliferative potential against a range of cancer types, with a favorable safety profile.
- The observed binding affinities and QSAR correlations provide insights into the structure-activity relationships governing their anticancer effects.
- Compound D11 emerges as a promising lead candidate for further development as a lung carcinoma therapeutic.
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