Antiproliferation, 3D-multicellular spheroid and VEGFR-2 inhibitory properties of spiroindolin-2-ones with phosphonate function

Hassan, Sara M., Farid, Alyaa, Bekheit, Mohamed S., Panda, Siva S., Kariuki, Benson M. ORCID: https://orcid.org/0000-0002-8658-3897, Abdelnaser, Anwar, Nasr, Soad, Fayad, Walid, El-Manawaty, May A., Soliman, Ahmed A. F. and Girgis, Adel S. 2025. Antiproliferation, 3D-multicellular spheroid and VEGFR-2 inhibitory properties of spiroindolin-2-ones with phosphonate function. Scientific Reports 15 (1) , 35018. 10.1038/s41598-025-20712-4

PDF - Published Version Available under License Creative Commons Attribution. Download (4MB)

Abstract

Spiroindolin-2-ones with phosphonate function 17a‒t (20 analogs, 96‒72% yield) were generated by microwave synthetic methodology using azomethine cycloaddition of the appropriate 3,5-bis(ylidene)-4-piperidone-1-phosphonate 14a‒g. Single crystal X-ray analysis of 17d confirmed the structure. Promising 2D-monolayer antiproliferation properties (MTT assay) were observed for some of the synthesized agents with no harm to normal (RPE1) cell line. Compound 17h (R = 4-ClC6H4, R′ = H; IC50 = 3.08 μM; 6.6- and 3.1-fold the standard drugs, 5-fluorouracil and sunitinib, respectively) is the most distinguished agent against colon/HCT116 cell line. Compound 17f (R = 4-FC6H4, R′ = Cl; IC50 = 5.252 μM; 3.2-fold the activity of sunitinib, the clinically approved standard drug) also has significant activity against pancreatic/PaCa2 cell line. 3D-multicellular spheroid (HCT116) testing was also performed. Notable VEGFR-2 inhibitory properties were evident for some of the synthesized analogs. Considerable activity against COX-1/-2 and TNF-α, relative to the established NSAIDs ibuprofen and indomethacin, was also detected. CAM testing evidenced the anti-VEGFR-2 observations and anti-angiogenic properties. Internal and external validated QSAR models explored the functions necessary for the antiproliferation potency. In conclusion, the designed spiroindolin-2-ones conjugated with phosphonate function can be useful for optimizing novel anti-cancer therapeutic agent(s) with anti-angiogenic (anti-VEGFR-2) mode of action after considering more needed advanced pharmacological studies.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Chemistry
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
Date of First Compliant Deposit:	13 October 2025
Date of Acceptance:	16 September 2025
Last Modified:	13 Oct 2025 11:30
URI:	https://orca.cardiff.ac.uk/id/eprint/181608

Actions (repository staff only)

Edit Item