Design, Synthesis of Novel Platinum(II) Glycoconjugates, and Evaluation of Their Antitumor Effects

Abstract

A new series of sugar-conjugated (trans-R, R-cyclohexane-1, 2-diamine)-2-halo-malonato-platinum(II) complexes were designed and synthesized to target tumor-specific glucose transporters (GLUTs). The water solubility of the sugar-conjugated platinum (II) complexes was greatly improved by average of 570-fold, 33-fold, and 94-fold, respectively, compared to cisplatin (1.0 mg/mL), carboplatin (17.1 mg/mL), and the newest generation of clinical drug oxaliplatin (6.0 mg/mL). Despite the high water solubility, the platinum(II) glycoconjugates exhibited a notable increase in cytotoxicity by a margin of 1.5- to 6.0-fold in six different human cancer cell lines with respect to oxaliplatin. The potential GLUT1 transportability of the complexes was investigated through a molecular docking study and was confirmed with GLUT1 inhibitor-mediated cytotoxicity dependency evaluation. The results showed that the sugar-conjugated platinum(II) complexes can be recognized by the glucose recognition binding site of GLUT1 and their cell killing effect depends highly on the GLUT1 inhibitor, quercetin. The research presenting a prospective concept for targeted therapy anticancer drug design, and with the analysis of the synthesis, water solubility, antitumor activity, and the transportability of the platinum(II) glycoconjugates, this study provides fundamental data supporting the inherent potential of these designed conjugates as lead compounds for GLUT-mediated tumor targeting.

Toward Multi-Targeted Platinum and Ruthenium Drugs—A New Paradigm in Cancer Drug Treatment Regimens?

“…The complexes exhibited comparable cytotoxicity irrespective of the sugar (glucose, mannose, and galactose) tethered, via the linker, to the platinum base against A549, HT29, A357, A431, ECA109, and SKOV3 cancer cells. 78 Their cytotoxicities were reduced significantly, as expected, in the presence of the GLUT inhibitor quercetin.…”

“…As before, all the complexes showed significantly improved solubility (by several orders of magnitude) over cisplatin, carboplatin, and oxaliplatin and exhibited enhanced cytotoxicity over oxaliplatin against GLUT-expressing cancer cells. 78 An in vivo study on the galactose complex, Gal-Pt (16a), Figure 3, showed it to be superior to cisplatin against a lung cancer mouse model and more effective than oxaliplatin against a colon cancer mouse model. 79 Of note is the fact that Gal-Pt (16a), Figure 3, was over 25 times more water-soluble compared to oxaliplatin, potentially making it easier to be excreted by the kidneys, thus reducing heavy metal accumulation and associated systemic toxicities.…”

Endothelial cell metabolism inhibition: A new approach to the treatment of resistant metastatic colorectal carcinoma

“…showed that sugar-conjugated platinum(II) complexes are recognized by the glucose recognition binding site of GLUT1 with desirable profiles for platinum-based drug design [23] .…”

Square-Planar vs. Trigonal Bipyramidal Geometry in Pt(II) Complexes Containing Triazole-Based Glucose Ligands as Potential Anticancer Agents

“…One of the most successful strategies is the introduction of bio-active molecules in the coordination environment of the metal, capable of increasing its versatility and selectivity [17,18]. Among these, sugars are an excellent example due to their biocompatibility, the possibility of modulating their chemico-physical properties, and the ability of selective recognition by cancer cells, known as the Warburg effect [19][20][21][22][23][24][25][26][27][28]. In this context, over the last few years, our research group has proposed new organometallic glycoconjugate platinum complexes as innovative anticancer agents [29][30][31][32][33].…”