Design, Synthesis, and Anti-Cervical Cancer and Reversal of Tumor Multidrug Resistance Activity of Novel Nitrogen-Containing Heterocyclic Chalcone Derivatives
This study involved the design and synthesis of 21 new nitrogen-containing heterocyclic chalcone derivatives utilizing the active substructure splicing principle, with glycyrrhiza chalcone serving as the lead compound. The targets of these derivatives were VEGFR-2 and P-gp, and their efficacy agains...
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MDPI AG
2023-06-01
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| Online Access: | https://www.mdpi.com/1420-3049/28/11/4537 |
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| author | Zheng Yang Zheng-Ye Liu Mourboul Ablise Aikebaier Maimaiti Zuohelaguli Mutalipu Yusupuwajimu Alimujiang Aizitiaili Aihaiti |
| author_facet | Zheng Yang Zheng-Ye Liu Mourboul Ablise Aikebaier Maimaiti Zuohelaguli Mutalipu Yusupuwajimu Alimujiang Aizitiaili Aihaiti |
| author_sort | Zheng Yang |
| collection | DOAJ |
| description | This study involved the design and synthesis of 21 new nitrogen-containing heterocyclic chalcone derivatives utilizing the active substructure splicing principle, with glycyrrhiza chalcone serving as the lead compound. The targets of these derivatives were VEGFR-2 and P-gp, and their efficacy against cervical cancer was evaluated. Following preliminary conformational analysis, compound <b>6f</b> ((E)-1-(2-hydroxy-5-((4-hydroxypiperidin-1-yl)methyl)-4-methoxyphenyl)-3-(4-((4-methylpiperidin-1-yl)methyl)phenyl)prop-2-en-1-one) exhibited significant antiproliferative activity against human cervical cancer cells (HeLa and SiHa) with IC<sub>50</sub> values of 6.52 ± 0.42 and 7.88 ± 0.52 μM, respectively, when compared to other compounds and positive control drugs. Additionally, this compound demonstrated lower toxicity towards human normal cervical epithelial cells (H8). Subsequent investigations have demonstrated that <b>6f</b> exerts an inhibitory impact on VEGFR-2, as evidenced by its ability to impede the phosphorylation of p-VEGFR-2, p-PI3K, and p-Akt proteins in HeLa cells. This, in turn, results in the suppression of cell proliferation and the induction of both early and late apoptosis in a concentration-dependent manner. Furthermore, <b>6f</b> significantly curtails the invasion and migration of HeLa cells. In addition, <b>6f</b> had an IC<sub>50</sub> of 7.74 ± 0.36 μM against human cervical cancer cisplatin-resistant HeLa/DDP cells and a resistance index (RI) of 1.19, compared to 7.36 for cisplatin HeLa cells. The combination of <b>6f</b> and cisplatin resulted in a significant reduction in cisplatin resistance in HeLa/DDP cells. Molecular docking analyses revealed that <b>6f</b> exhibited binding free energies of −9.074 and −9.823 kcal·mol<sup>−1</sup> to VEGFR-2 and P-gp targets, respectively, and formed hydrogen bonding forces. These findings suggest that <b>6f</b> has potential as an anti-cervical cancer agent and may reverse cisplatin-resistant activity in cervical cancer. The introduction of the 4-hydroxy piperidine and 4-methyl piperidine rings may contribute to its efficacy, and its mechanism of action may involve dual inhibition of VEGFR-2 and P-gp targets. |
| first_indexed | 2024-03-11T03:00:17Z |
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| language | English |
| last_indexed | 2024-03-11T03:00:17Z |
| publishDate | 2023-06-01 |
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| spelling | doaj.art-058a74d812c643ceb600356a524a617d2023-11-18T08:17:57ZengMDPI AGMolecules1420-30492023-06-012811453710.3390/molecules28114537Design, Synthesis, and Anti-Cervical Cancer and Reversal of Tumor Multidrug Resistance Activity of Novel Nitrogen-Containing Heterocyclic Chalcone DerivativesZheng Yang0Zheng-Ye Liu1Mourboul Ablise2Aikebaier Maimaiti3Zuohelaguli Mutalipu4Yusupuwajimu Alimujiang5Aizitiaili Aihaiti6College of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaCollege of Pharmacy, Xinjiang Medical University, Urumqi 830011, ChinaThis study involved the design and synthesis of 21 new nitrogen-containing heterocyclic chalcone derivatives utilizing the active substructure splicing principle, with glycyrrhiza chalcone serving as the lead compound. The targets of these derivatives were VEGFR-2 and P-gp, and their efficacy against cervical cancer was evaluated. Following preliminary conformational analysis, compound <b>6f</b> ((E)-1-(2-hydroxy-5-((4-hydroxypiperidin-1-yl)methyl)-4-methoxyphenyl)-3-(4-((4-methylpiperidin-1-yl)methyl)phenyl)prop-2-en-1-one) exhibited significant antiproliferative activity against human cervical cancer cells (HeLa and SiHa) with IC<sub>50</sub> values of 6.52 ± 0.42 and 7.88 ± 0.52 μM, respectively, when compared to other compounds and positive control drugs. Additionally, this compound demonstrated lower toxicity towards human normal cervical epithelial cells (H8). Subsequent investigations have demonstrated that <b>6f</b> exerts an inhibitory impact on VEGFR-2, as evidenced by its ability to impede the phosphorylation of p-VEGFR-2, p-PI3K, and p-Akt proteins in HeLa cells. This, in turn, results in the suppression of cell proliferation and the induction of both early and late apoptosis in a concentration-dependent manner. Furthermore, <b>6f</b> significantly curtails the invasion and migration of HeLa cells. In addition, <b>6f</b> had an IC<sub>50</sub> of 7.74 ± 0.36 μM against human cervical cancer cisplatin-resistant HeLa/DDP cells and a resistance index (RI) of 1.19, compared to 7.36 for cisplatin HeLa cells. The combination of <b>6f</b> and cisplatin resulted in a significant reduction in cisplatin resistance in HeLa/DDP cells. Molecular docking analyses revealed that <b>6f</b> exhibited binding free energies of −9.074 and −9.823 kcal·mol<sup>−1</sup> to VEGFR-2 and P-gp targets, respectively, and formed hydrogen bonding forces. These findings suggest that <b>6f</b> has potential as an anti-cervical cancer agent and may reverse cisplatin-resistant activity in cervical cancer. The introduction of the 4-hydroxy piperidine and 4-methyl piperidine rings may contribute to its efficacy, and its mechanism of action may involve dual inhibition of VEGFR-2 and P-gp targets.https://www.mdpi.com/1420-3049/28/11/4537azacyclicglycyrrhiza chalconeanti-cervical cancer activitycisplatin resistancemolecular docking |
| spellingShingle | Zheng Yang Zheng-Ye Liu Mourboul Ablise Aikebaier Maimaiti Zuohelaguli Mutalipu Yusupuwajimu Alimujiang Aizitiaili Aihaiti Design, Synthesis, and Anti-Cervical Cancer and Reversal of Tumor Multidrug Resistance Activity of Novel Nitrogen-Containing Heterocyclic Chalcone Derivatives Molecules azacyclic glycyrrhiza chalcone anti-cervical cancer activity cisplatin resistance molecular docking |
| title | Design, Synthesis, and Anti-Cervical Cancer and Reversal of Tumor Multidrug Resistance Activity of Novel Nitrogen-Containing Heterocyclic Chalcone Derivatives |
| title_full | Design, Synthesis, and Anti-Cervical Cancer and Reversal of Tumor Multidrug Resistance Activity of Novel Nitrogen-Containing Heterocyclic Chalcone Derivatives |
| title_fullStr | Design, Synthesis, and Anti-Cervical Cancer and Reversal of Tumor Multidrug Resistance Activity of Novel Nitrogen-Containing Heterocyclic Chalcone Derivatives |
| title_full_unstemmed | Design, Synthesis, and Anti-Cervical Cancer and Reversal of Tumor Multidrug Resistance Activity of Novel Nitrogen-Containing Heterocyclic Chalcone Derivatives |
| title_short | Design, Synthesis, and Anti-Cervical Cancer and Reversal of Tumor Multidrug Resistance Activity of Novel Nitrogen-Containing Heterocyclic Chalcone Derivatives |
| title_sort | design synthesis and anti cervical cancer and reversal of tumor multidrug resistance activity of novel nitrogen containing heterocyclic chalcone derivatives |
| topic | azacyclic glycyrrhiza chalcone anti-cervical cancer activity cisplatin resistance molecular docking |
| url | https://www.mdpi.com/1420-3049/28/11/4537 |
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