Data_Sheet_1_Protected and De-protected Platinum(IV) Glycoconjugates With GLUT1 and OCT2-Mediated Selective Cancer Targeting: Demonstrated Enhanced Transporter-Mediated Cytotoxic Properties in vitro and in vivo.PDF

Physiological characteristics of human malignancies are increased glycolysis and overexpression of glucose transporters (GLUTs). ¹⁸Flurodeoxyglucose-positron emission tomography (FDG-PET) has successfully developed as clinical modality for the diagnosis and staging of many cancers based on the Warburg effect. To leverage this glucose transporter mediated metabolic disparity between normal and malignant cells, in the current report, protected, and de-protected glucose, mannose, galactose, rhamnose, maltose, and lactose-conjugated platinum(IV) complexes were designed and synthesized. The suggested potential of facilitated intravenous to oral switching of glycosylated platinum(IV) prodrugs with cancer-targeting properties were evaluated for glucose transporter 1 (GLUT1) and organic cation transporter 2 (OCT2)-mediated selective properties in vitro and in vivo. The cytotoxicity of 2d, 5d, and 6d were ~23-fold greater than that of the positive controls cisplatin, oxaliplatin, and satraplatin, respectively. The leading compound 6d, the IC₅₀ of which with the GLUT1 inhibitor 4,6-oethylidene-α-D-glucose (EDG) and phloretin (31.80 and 38.71 μM) are 36- and 44-folds higher, respectively, than the 48 h IC₅₀ (0.89 μM), is superior to the reported 5-8, exhibiting enhanced cancer targeting. The compounds also showed reduced toxicity to normal cells (293T IC₅₀ = 12.06 μM and 3T3 cells IC₅₀ > 100 μM) and exhibited no cross-resistance to cisplatin. Moreover, the encouraging selectivity of 6d for MCF-7 cells in vivo indicated that the pyranoside performs an important function in cancer targeting.