Glycosylated ancillary ligand bearing Pt(II) anticancer complexes: In vitro and in vivo anticancer evaluation and EMT inhibition in triple-negative breast cancer.

Warburg's effect and elevated glucose transporter (GLUT) activity are defining features of many tumors and offer a route for selective drug delivery. We synthesized a panel of monosaccharide (mannose)-functionalized Pt(II) complexes (C1-C8) along with a non-glycosylated control (C9) and elucidated their structures by multiple analytical techniques and single-crystal X-ray diffraction analysis (C7, C9). Time-dependent 1H NMR indicated a water-assisted release of the mannose functionalize co-ligand from the Pt(II) center. Biological testing in MCF-7 (ER+), HeLa, and MDA-MB-231 (triple-negative) cells identified C3 and C7 as the most active compounds, suppressing cell proliferation and cell migration while inducing marked cytotoxicity. Inhibition of GLUT1 substantially diminished the effect of C3, consistent with transporter-mediated uptake. Mechanistic assays showed that C3 activates caspase-3, lowers Bcl-2 and Bcl-XL expression, and attenuates epithelial-mesenchymal transition markers, pointing to apoptosis induction and reduced metastatic potential. In a TNBC mouse model, C3 curtailed primary tumor growth, limited metastatic burden, and extended survival without detectable hematologic or histologic toxicity. Taken together, these results nominate C3 as a mannose-functionalized Pt(II) candidate that exploits GLUT1 overexpression to concentrate drug in cancer cells while promoting apoptosis and restraining EMT. This functionalized based platinum approach provides a practical path toward targeted therapy for difficult breast cancer subtypes, particularly triple-negative disease.