Design, Synthesis,Bioactivity Evaluation And Mechanism Study Of Novel Platinum Antitumor Agents Targeting GLUT1

Platinum anticancer drugs cisplatin,carboplatin and oxaliplatin have become the most potent metal-containing drugs widely used for cancer chemotherapy.However,poor water solubility,drug resistance and severe side effects greatly limit the clinical application.Therefore,improvements to increase solubility,avoid drug resistance and reduce the toxic side effects have drawn extensive research efforts.Compared to normal cells,cancer cells have high rates of aerobic glycolysis and increased glucose consumption.Today this phenomenon is known as the Warburg Effect.Glucose transporter GLUT1 is widely overexpressed in cancer cells to incorporate enhanced sugar uptake,which makes it an ideal target for tumor-targeted drug design.With the aim of developing a new class of selective tumor-targeting platinum?II?anticancer agent,our principal interest is to target the GLUT1 mediated Warburg effect as an anticancer strategy.In the current report,we focus on the sugar-conjugated platinum?II?complexes for a comprehensive evaluation on their antitumor activity,transmembrane transport mechanism,and antitumor mechanism.Based on our design concept,we select glucose,mannose,galactose and 2-deoxy glucose as the sugar moity.We synthesized 15 platinum complexes by the methods of glycoconjugation at the malonato leaving ligand,confirmed their chemical structure by ¹H NMR,¹³C NMR and MS spectrum.The in vitro cytotoxicity of 15 platinum complexes was tested and the results indicated that platinum complex 6e exhibited excellent antitumor activity.In addition,platinum complex 6e showed no cross-resistance to cisplatin and performed outstanding tumor selectivity.GLUT1inhibitor mediated cell viability analysis,GLUT1 knockdown cell line-based cytotoxicity assessment,and platinum accumulation study demonstrated that the cellular uptake of the sugar-conjugates was regulated by GLUT1.The mechanistic origin of the antitumor effect of the sugar-conjugated platinum complexes was found to be forming the bifunctional Pt-guanine-guanine?Pt-GG?intrastrand cross-links with DNA.Results from qRT-PCR and western blot indicated that these platinum complexes could induce apoptosis and cause cell death.In the in vivo experiments,platinum complex 6e monotherapy yielded 44.68%inhibition of tumor growth in HT29 bearing Balb/c nude mice,indicating promising in vivo antitumor activity.In vitro synergistic antitumor activity of platinum complex 6e with folinic acid?FA?and5-fluorouracil?5-FU?respectively or a fixed three-component FOFLOX combination has been measured and compared with oxaliplatin.Cell cycle analysis demonstrated that platinum complex 6e could induce cell cycle arrest in the G₁ phase.These results indicated that combination with FA and 5-FU may result in improved efficacy over traditional FOLFOX regimen.In summary,we designed and synthesized a series of sugar-conjugated platinum complexes with enhanced water solubility and improved tumor selectivity.The study provides fundamental data supporting the potential of GLUT1 as an antitumor target.The glucose-conjugated platinum complex 6e was found to be an antitumor candidate for further?pre?clinical development.