2-Deoxyglucose conjugated platinum (II) complexes for targeted therapy: design, synthesis, and antitumor activity

Abstract

Malignant neoplasms exhibit an elevated rate of glycolysis over normal cells. To target the Warburg effect, we designed a new series of 2-deoxyglucose (2-DG) conjugated platinum (II) complexes for glucose transporter 1 (GLUT1)-mediated anticancer drug delivery. The potential GLUT1 transportability of the complexes was investigated through a comparative molecular docking analysis utilizing the latest GLUT1 protein crystal structure. The key binding site for 2-DG as GLUT1's substrate was identified with molecular dynamics simulation, and the docking study demonstrated that the 2-DG conjugated platinum (II) complexes can be recognized by the same binding site as potential GLUT1 substrate. The conjugates were synthesized and evaluated for in vitro cytotoxicity study with seven human cancer cell lines. The results of this study revealed that 2-DG conjugated platinum (II) complexes are GLUT1 transportable substrates and exhibit improved cytotoxicities in cancer cell lines that over express GLUT1 when compared to the clinical drug, Oxaliplatin. The correlation between GLUT1 expression and antitumor effects are also confirmed. The study provides fundamental information supporting the potential of the 2-DG conjugated platinum (II) complexes as lead compounds for further pharmaceutical R&D.

Metal complexes in cancer therapy – an update from drug design perspective

“…GLUTI1 was evaluated for its potential to transport the drug complex with the aid of comparative molecular docking analysis using the latest GLUTI crystal structure. Molecular dynamics (MD) was used in identifying the key binding site of 2-DG as a substrate for GLUTI 38. The findings from the docking result revealed that the 2-DG conjugated platinum complex can bind to the same binding site as the GLUTI substrate 38.…”

“…Molecular dynamics (MD) was used in identifying the key binding site of 2-DG as a substrate for GLUTI 38. The findings from the docking result revealed that the 2-DG conjugated platinum complex can bind to the same binding site as the GLUTI substrate 38. This led to the synthesis of the conjugate (a) and (b) and were evaluated for their cytotoxicity.…”

Characterization of a putative ArsR transcriptional regulator encoded by Rv2642 from Mycobacterium tuberculosis

“…Many metal ions are indispensable for cellular functions such as respiration, redox homeostasis and gene transcription (Andreini, Bertini, Cavallaro, Holliday, & Thornton, 2008;Qian et al, 2015). However, excess metals are detrimental due to the metal catalyzed formation of hydroxyl radicals that can react with lipids, protein and DNA through Fenton reaction (Halliwell & Gutteridge, 1984).…”

CuII and AuIII Complexes with Glycoconjugated Dithiocarbamato Ligands for Potential Applications in Targeted Chemotherapy

“…In recent years, this histopathological behavior was exploited by a few research groups, in particular those of Gao and Lippard, who conjugated oxaliplatin to functionalized monosaccharides at different positions of the pyranose ring and tested the obtained Pt II complexes for anticancer properties with promising results.…”