Integration of Hybridization Strategies in Pyridine–Urea Scaffolds for Novel Anticancer Agents: Design, Synthesis, and Mechanistic Insights

Sreenivasulu Godesi, Hossam Nada, Joohan Lee, Joon Hee Kang, Soo Youl Kim, Yongseok Choi, Kyeong Lee

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

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 8a, specifically, exhibited an impressive GI50 value of 0.06 μM against the MCF7 cancer cell line, while compound 8h displayed the highest cytotoxic activity against the HCT116 cell line, with a GI50 of 0.33 ± 0.042 μM. Notably, compounds 8a, 8h, and 8i 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.

Original languageEnglish
Article number4952
JournalMolecules
Volume28
Issue number13
DOIs
Publication statusPublished - 2023 Jul

Bibliographical note

Funding Information:
This study was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) no. 2018R1A5A2023127 and no. 2023R1A2C3004599. This work is also supported by the BK21 FOUR program, which was funded by the Ministry of Education of Korea through NRF.

Publisher Copyright:
© 2023 by the authors.

Keywords

  • anticancer agents
  • hybridization strategy
  • MM–GBSA
  • molecular docking
  • molecular dynamics
  • pyridine–urea

ASJC Scopus subject areas

  • Analytical Chemistry
  • Chemistry (miscellaneous)
  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery
  • Physical and Theoretical Chemistry
  • Organic Chemistry

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