Integration of Hybridization Strategies in Pyridine–Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights
Annually, millions of new cancer cases are reported, leading to millions of deaths worldwide. Among the newly reported cases, breast and colon cancers prevail as the most frequently detected variations. To effectively counteract this rapid increase, the development of innovative therapies is crucial...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-06-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/13/4952 |
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| author | Sreenivasulu Godesi Hossam Nada Joohan Lee Joon-Hee Kang Soo-Youl Kim Yongseok Choi Kyeong Lee |
| author_facet | Sreenivasulu Godesi Hossam Nada Joohan Lee Joon-Hee Kang Soo-Youl Kim Yongseok Choi Kyeong Lee |
| author_sort | Sreenivasulu Godesi |
| collection | DOAJ |
| description | Annually, millions of new cancer cases are reported, leading to millions of deaths worldwide. Among the newly reported cases, breast and colon cancers prevail as the most frequently detected variations. To effectively counteract this rapid increase, the development of innovative therapies is crucial. Small molecules possessing pyridine and urea moieties have been reported in many of the currently available anticancer agents, especially VEGFR2 inhibitors. With this in mind, a rational design approach was employed to create hybrid small molecules combining urea and pyridine. These synthesized compounds underwent in vitro testing against breast and colon cancer cell lines, revealing potent submicromolar anticancer activity. Compound <b>8a</b>, specifically, exhibited an impressive GI<sub>50</sub> value of 0.06 μM against the MCF7 cancer cell line, while compound <b>8h</b> displayed the highest cytotoxic activity against the HCT116 cell line, with a GI<sub>50</sub> of 0.33 ± 0.042 μM. Notably, compounds <b>8a</b>, <b>8h</b>, and <b>8i</b> demonstrated excellent safety profiles when tested on normal cells. Molecular docking, dynamic studies, and free energy calculations were employed to validate the affinity of these compounds as VEGFR2 inhibitors. |
| first_indexed | 2024-03-11T01:34:19Z |
| format | Article |
| id | doaj.art-89e2dd38bdae41cfa6c7cc6eeb995e4f |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-11T01:34:19Z |
| publishDate | 2023-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-89e2dd38bdae41cfa6c7cc6eeb995e4f2023-11-18T17:06:01ZengMDPI AGMolecules1420-30492023-06-012813495210.3390/molecules28134952Integration of Hybridization Strategies in Pyridine–Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic InsightsSreenivasulu Godesi0Hossam Nada1Joohan Lee2Joon-Hee Kang3Soo-Youl Kim4Yongseok Choi5Kyeong Lee6BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of KoreaBK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of KoreaBK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of KoreaGraduate School of Cancer Science and Policy, National Cancer Center, Goyang 10408, Republic of KoreaDivision of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, Republic of KoreaCollege of Biosciences and Biotechnology, Korea University, Seoul 02841, Republic of KoreaBK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of KoreaAnnually, millions of new cancer cases are reported, leading to millions of deaths worldwide. Among the newly reported cases, breast and colon cancers prevail as the most frequently detected variations. To effectively counteract this rapid increase, the development of innovative therapies is crucial. Small molecules possessing pyridine and urea moieties have been reported in many of the currently available anticancer agents, especially VEGFR2 inhibitors. With this in mind, a rational design approach was employed to create hybrid small molecules combining urea and pyridine. These synthesized compounds underwent in vitro testing against breast and colon cancer cell lines, revealing potent submicromolar anticancer activity. Compound <b>8a</b>, specifically, exhibited an impressive GI<sub>50</sub> value of 0.06 μM against the MCF7 cancer cell line, while compound <b>8h</b> displayed the highest cytotoxic activity against the HCT116 cell line, with a GI<sub>50</sub> of 0.33 ± 0.042 μM. Notably, compounds <b>8a</b>, <b>8h</b>, and <b>8i</b> demonstrated excellent safety profiles when tested on normal cells. Molecular docking, dynamic studies, and free energy calculations were employed to validate the affinity of these compounds as VEGFR2 inhibitors.https://www.mdpi.com/1420-3049/28/13/4952hybridization strategypyridine–ureaanticancer agentsmolecular dockingmolecular dynamicsMM–GBSA |
| spellingShingle | Sreenivasulu Godesi Hossam Nada Joohan Lee Joon-Hee Kang Soo-Youl Kim Yongseok Choi Kyeong Lee Integration of Hybridization Strategies in Pyridine–Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights Molecules hybridization strategy pyridine–urea anticancer agents molecular docking molecular dynamics MM–GBSA |
| title | Integration of Hybridization Strategies in Pyridine–Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights |
| title_full | Integration of Hybridization Strategies in Pyridine–Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights |
| title_fullStr | Integration of Hybridization Strategies in Pyridine–Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights |
| title_full_unstemmed | Integration of Hybridization Strategies in Pyridine–Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights |
| title_short | Integration of Hybridization Strategies in Pyridine–Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights |
| title_sort | integration of hybridization strategies in pyridine urea scaffolds for novel anticancer agents design synthesis and mechanistic insights |
| topic | hybridization strategy pyridine–urea anticancer agents molecular docking molecular dynamics MM–GBSA |
| url | https://www.mdpi.com/1420-3049/28/13/4952 |
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