TY - JOUR
T1 - Integration of Hybridization Strategies in Pyridine–Urea Scaffolds for Novel Anticancer Agents
T2 - Design, Synthesis, and Mechanistic Insights
AU - Godesi, Sreenivasulu
AU - Nada, Hossam
AU - Lee, Joohan
AU - Kang, Joon Hee
AU - Kim, Soo Youl
AU - Choi, Yongseok
AU - Lee, Kyeong
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/7
Y1 - 2023/7
N2 - 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.
AB - 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.
KW - anticancer agents
KW - hybridization strategy
KW - MM–GBSA
KW - molecular docking
KW - molecular dynamics
KW - pyridine–urea
UR - http://www.scopus.com/inward/record.url?scp=85164843671&partnerID=8YFLogxK
U2 - 10.3390/molecules28134952
DO - 10.3390/molecules28134952
M3 - Article
C2 - 37446614
AN - SCOPUS:85164843671
SN - 1420-3049
VL - 28
JO - Molecules
JF - Molecules
IS - 13
M1 - 4952
ER -