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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\u2009=\u20094-ClC<jats:sub>6<\/jats:sub>H<jats:sub>4<\/jats:sub>, R\u2032\u2009=\u2009H; IC<jats:sub>50<\/jats:sub>\u2009=\u20093.08\u00a0\u03bcM; 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\u2009=\u20094-FC<jats:sub>6<\/jats:sub>H<jats:sub>4<\/jats:sub>, R\u2032\u2009=\u2009Cl; IC<jats:sub>50<\/jats:sub>\u2009=\u20095.252\u00a0\u03bcM; 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-\u03b1, 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.<\/jats:p>","DOI":"10.1038\/s41598-025-20712-4","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T19:41:22Z","timestamp":1759866082000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Antiproliferation, 3D-multicellular spheroid and VEGFR-2 inhibitory properties of spiroindolin-2-ones with phosphonate function"],"prefix":"10.1038","volume":"15","author":[{"given":"Sara M.","family":"Hassan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyaa","family":"Farid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed S.","family":"Bekheit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siva S.","family":"Panda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benson M.","family":"Kariuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anwar","family":"Abdelnaser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soad","family":"Nasr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walid","family":"Fayad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May A.","family":"El-Manawaty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed A. 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