Anticancer Property And Mechanism Studies Of Corannulene Derivatives As Selective Tumor Targeting Agents

Corannulene,is a non-planar Polycyclic Aromatic Hydrocarbons(PAH)and has a unique bowl-shaped geometry.Based on its polarized ?-electron system,corannulene possesses many special optical,electronic and magnetic properties.After over 40 years from corannulene has been discovered,Jay Siegel successfully developed a process for kilogram-scale synthesis of corannulene in 2012,and this has greatly progressed the research of corannulene and its derivatives in the field of molecular carbonaceous materials.Due to the very low water solubility and physiological incompatibility of corannulene molecule,studies and applications of corannulene compounds remains very challenging and a relatively unexplored field.In this thesis,we have identified a novel series of glycoconjugated corannulene derivatives with improved biocompatibility and explored their physicochemical and pharmacological properties as potential tumor targeting agents.The scientific accomplishments of the research include the following topics:1.Based on tumor-specific glucose transporter(GLUT)-mediated Warburg effect,a series of different sugar conjugated corannulene ?-bowl derivatives are designed and synthesized.2.Cell-based cytotoxicity studies against a panel of human cancer cell lines areinvestigated and evaluation of in vivo efficacy using a xenograft model ofzebrafish bearing A549 tumors has performed.3.GLUT-mediated cellular uptake mechanism of the designer corannulene-sugarconjugates has investigated using GLUT1 overexpress cell line with confocal fluorescence microscopy.4.The DNA-interaction property and the tumor targeting mechanisms of thecorannulene derivatives have been explored and deciphered by means offluorescence quenching,micro scale thermophoresis(MST),isothermo titrationcalorimetry(ITC)as well as molecular dynamics simulation technologies.In summary,the research has identified a new series of corannulene ?-bowls by combining the hydrophobic molecule along with triazole-linked glucose,mannose and galactose to augment the aqueous solubility,promote the GLUT-mediated cellular uptake and trigger the intracellular anticancer cvents.Comprehensive analysis revealed that the Cor-sugar compounds exploit tumor-specific glucose transporters by leveraging the Warburg effect for selective tumor targeting.Most importantly,the external DNA-binding interaction and the DNA-intercalating effect of the bowl-shaped Cor-sugars have been demonstrated for the first time,and this appears to be one of the key features in the mechanism for their significant anticancer activity.