From design to activity: Linker flexibility in 3-spiro-2-oxindoline VEGFR-2 inhibitors

Title : From design to activity: Linker flexibility in 3-spiro-2-oxindoline VEGFR-2 inhibitors

Abstract:

A series of novel 3-spiro-2-oxindoline derivatives incorporating an aromatic hydrazide linker were rationally designed and synthesized as potential VEGFR-2 inhibitors. This work specifically aimed to evaluate the influence of linker rigidity on biological activity, in comparison with previously reported aliphatic counterparts exhibiting greater conformational flexibility. Molecular docking studies indicated favorable binding interactions within the VEGFR-2 active site, including key hydrogen bonding and hydrophobic contacts. However, in vitro antiproliferative evaluation against HepG2 and HCT116 cancer cell lines revealed that most aromatic derivatives displayed diminished cytotoxic activity relative to their aliphatic analogues.

Notably, selected compounds retained significant VEGFR-2 inhibitory activity, with compound 8g demonstrating the highest potency among the series. Further mechanistic investigations showed that active compounds induced G₀/G₁ phase cell cycle arrest and promoted apoptotic cell death, confirming their mode of action at the cellular level. Preliminary structure activity relationship (SAR) analysis suggested that increased linker rigidity compromises conformational adaptability within the binding pocket, thereby negatively impacting biological performance.

Overall, these findings underscore the critical role of linker flexibility in optimizing VEGFR-2 inhibition and provide valuable insights for the rational design of more potent and biologically effective anticancer agents.

Biography:

Prof. Tarek Aboul-Fadl has completed his PhD in Medicinal Chemistry from Assiut University, Egypt (1994) under the channel system and joint supervision scheme between Assiut University and Josai University/Japan. He performed his postdoctoral training as a postdoctoral research fellow and scientist of Pharmaceutical and Medicinal Chemistry at University of Vienna, Austria (1997- 1998), Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany (1999 and 2013) and University of Utah, USA (2001-2002 and 2004-2005).  He has over 88 publications and 4 patents that have been cited over 2448 times, and his publication H-index is 27 (google_scholar), 23(Scopus).  He was awarded ACDIMA Research Award for the Best Scientific Research in Arab World, 2012. He was listed in the World's 2% Top-Cited Scientists by Stanford University for three successive years (2021-2024).