![\"\"](\"https:\/\/sites.unica.it\/pe2026\/files\/2026\/05\/Foto_OnaliA-950x1024.png\")
<\/figure>PC26 – Alessia Onali<\/strong><\/p>\n\n\n\n University of Cagliari, Italy<\/p>\n\n\n\n LinkedIn<\/a><\/strong> –<\/strong> ORCID<\/a><\/strong> PC26 – Alessia Onali University of Cagliari, Italy LinkedIn – ORCIDalessia.onali@unica.it Novel Thiazolidinone-Isatin Hybrids as Potent hCA IX Inhibitors Enhance Doxorubicin-Induced Apoptosis in Hypoxic Glioblastoma Cells Onali Alessia1, Guarnieri Lorenza2, Bosco Francesca2, Lupia Antonio1, Sanna Erica1, […]<\/p>\n","protected":false},"author":10371,"featured_media":0,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[1],"tags":[],"class_list":["post-2180","post","type-post","status-publish","format-standard","hentry","category-senza-categoria"],"_links":{"self":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/2180","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/users\/10371"}],"replies":[{"embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/comments?post=2180"}],"version-history":[{"count":7,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/2180\/revisions"}],"predecessor-version":[{"id":2569,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/posts\/2180\/revisions\/2569"}],"wp:attachment":[{"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/media?parent=2180"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/categories?post=2180"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/sites.unica.it\/pe2026\/wp-json\/wp\/v2\/tags?post=2180"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
alessia.onali@unica.it<\/strong><\/p>\n<\/div><\/div>\n\n\n\nNovel Thiazolidinone-Isatin Hybrids as Potent hCA IX Inhibitors Enhance Doxorubicin-Induced Apoptosis in Hypoxic Glioblastoma Cells<\/em><\/strong><\/td><\/tr> Onali Alessia1<\/sup>, Guarnieri Lorenza2<\/sup>, Bosco Francesca2<\/sup>, Lupia Antonio1<\/sup>, Sanna Erica1<\/sup>, Demuru Laura1, <\/sup>Atzeni Giulia1<\/sup>, Meleddu Rita1<\/sup>, Cottiglia Filippo1<\/sup>, Supuran T.Claudiu3<\/sup>, Distinto Simona1<\/sup>, Maccioni Elias1<\/sup><\/em>
1 <\/sup>Department of Life and Environmental Sciences, University of Cagliari, 09042 Monserrato, Italy
2 <\/sup>Section of Pharmacology, Department of Health Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy
3<\/sup> Dipartimento NEUROFARBA, Sezione di Scienze Farmaceutiche, Universit\u00e0 degli Studi di Firenze, Sesto Fiorentino, Florence, Italy<\/td><\/tr>Abstract<\/strong>
Carbonic anhydrase IX (hCA IX) is a HIF-1\u03b1-regulated transmembrane zinc-metalloenzyme overexpressed in hypoxic solid tumors, where it promotes extracellular acidification, invasive migration, and chemoresistance [1]. Its overexpression in glioblastoma multiforme (GBM) correlates with poor prognosis [2,3], yet no hCA IX inhibitor has reached clinical approval, underscoring the need for potent, isoform-selective compounds.
Applying a molecular hybridization strategy based on the tail approach, we designed and synthesized a series of thiazolidinone-isatin hybrids (3a-i, 4a-i) featuring a benzenesulfonamide zinc-binding group coupled to an extended tail projected into the mid-cavity and entrance regions of the hCA IX active site. Enzymatic assays identified compound\u00a03f<\/strong>\u00a0as the most potent and selective hCA IX inhibitor (Ki = 8.6 nM; SI hCAI\/IX = 631; SI hCAII\/IX = 32.7). N-acetylation of the sulfonamide nitrogen completely abolished activity across all derivatives (Ki > 10,000 nM), confirming the free -SO\u2082NH\u2082 as strictly required for Zn\u00b2\u207a coordination. Molecular docking confirmed coordination of the catalytic zinc ion and key hydrogen bond interactions with Gln92, Thr199, and Thr200.
In T98G glioblastoma cells, 3f (5 \u00b5M, non-cytotoxic as single agent) significantly sensitized cells to doxorubicin under both normoxic and chemically-induced hypoxic conditions (CoCl\u2082), reducing viability from ~76% to ~39%. Western blot analysis confirmed activation of the intrinsic apoptotic pathway, evidenced by increased Bax\/Bcl-2 and cleaved caspase-3 ratios. These findings establish 3f as a promising lead for CA IX-targeted antitumor strategies in chemoresistant glioblastoma.![\"\"](\"http:\/\/sites.unica.it\/pe2026\/files\/2026\/05\/Onali-Fig1-1-scaled.png\")
Figure 1. <\/strong>Hypoxia model validation and antiproliferative activity of 3f in T98G glioblastoma cells.
Data are expressed as mean \u00b1 SEM. **p < 0.01, ***p < 0.001 vs CTRL.<\/td><\/tr>References \u00a0<\/strong>
[1] Supuran, C.T., Carbonic anhydrase inhibitors and activators for novel therapeutic applications.<\/em> Future Med Chem, 2011. 3<\/strong>(9): p. 1165-80.
[2] Stupp, R., et al., Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.<\/em> N Engl J Med, 2005. 352<\/strong>(10): p. 987-96.
[3] Proescholdt, M.A., et al., Function of carbonic anhydrase IX in glioblastoma multiforme.<\/em> Neuro-Oncology, 2012. 14(11): p. 1357-1366.<\/td><\/tr><\/tbody><\/table><\/div><\/figure>\n","protected":false},"excerpt":{"rendered":"