Warburg Effect Targeted Novel Pt-antitumor Agents:Synthesis,Selective Drug Delivery And SAR

Cancer,also known as malignant tumor,is a large group of diseases that seriously threaten human health and is characterized by unregulated cell growth and excessive cell metabolism,invasion and metastasis.Due to population growth and population aging,the incidence and death rate of global cancers continue to increase.In 2018,18.1 million new cancer patients and 9.6 million people died of cancer.malignant tumor has become the second largest disease after the cardiovascular and cerebrovascular diseases.The main treatment methods for cancer are surgery,radiotherapy,chemotherapy and biological therapy.Among them,chemical drug therapy is a very important link.Among them,platinum antitumor drugs represented by cisplatin,carboplatin,and oxaliplatin are the most commonly used drugs in clinical malignant tumor chemotherapy.Although platinum drugs have strong antitumor activity,broad anticancer spectrum,and have good complementarity with other antitumor drugs,platinum antitumor drugs have low solubility,serious toxic side effects and drug resistance,and lack of targeting.These problems make it very limited in clinical application.Therefore,the key to the development and design of new platinum antitumor drugs is to solve the above-mentioned clinical deficiencies and achieve the targeted administration of platinum-based antitumor drugs.Compared with normal cells,tumor cells energize themselves through glycolysis,which has a relatively low production efficiency,and to maintain their own rapid growth,reproduction and metastasis needs,even under oxygen-rich conditions.This is the Warburg effect.According to the Warburg effect,the surface of tumor cells will overexpress glucose transporters to meet their metabolic needs for glucose,and provide more energy sources and energy carriers for the growth and reproduction of tumor cells.GLUT1 is the most distributed in human glucose transporters.And GLUT1 is overexpressed in many malignant tumors,such as breast cancer,colon cancer,liver cancer,gastric cancer,non-small cell lung cancer,and so on.Therefore,GLUT1 is widely used to study targeted glucose metabolism and develop targeted antitumor drugs.The mechanism of action of platinum antitumor drugs mainly involves two aspects,one is to react with DNA,and the other is to react with other components in the cell.After the platinum drugs enter the cell,hydration dissociation occurs according to the cellular environment.The platinum drugs dissociate and lose the leaving ligand,and then combine with water molecules to form a hydrate.The hydrates interact with N7 position of the guanine and adenine on DNA by electrostatic interaction,combined with DNA to form Pt-DNA adducts,which prevents DNA replication and transcription,and causes cells to die.This is the main pathway for the antitumor effect of platinum drugs.There are three main types of adducts formed by the combination of platinum drugs and DNA,Pt-DNA intrastrand cross-linking,Pt-DNA interstrand cross-linking and protein-Pt-DNA interstrand cross-linking.And compared with cisplatin,although oxaliplatin binds to DNA to form an adduct at a slower rate,Pt-DNA adduct formed by oxaliplatin is larger in volume,more hydrophobic and more toxic.After platinum drugs enter the cell,in addition to reacting with DNA to exert antitumor effects,they will also react with other biological macromolecules in the cell.Before the platinum drugs react with DNA,they may react with thiol-containing biomolecules such as glutathione and other metallothioneins,resulting in a decrease in the reaction between platinum drugs and DNA,inactivation of platinum drugs and enhanced cell detoxification.And finally bring about drug resistance.There are four main reasons for platinum-based drug resistance.In addition to the above reactions with thiol-containing biomolecules,there are three other reasons:（1）Reduction of platinum-based drug accumulation in cells.This can be achieved by reducing drug intake and increasing drug excretion.（2）The ability to repair DNA damage is enhanced,and the cell’s tolerance to damaged DNA is enhanced.DNA damage repair is mainly to remove damaged or inappropriate bases in DNA through nuclear excision repair technology.In addition,mismatch repair,base excision repair and double-strand repair can all repair DNA damage.（3）The apoptosis signal pathway is inhibited,which involves the expression of a variety of tumor suppressor proteins,pro-apoptotic proteins and anti-apoptotic proteins.It is precisely due to the lack of selectivity and specificity of platinum drugs that they will cause some toxic side effects and drug resistance of platinum drugs.Therefore,in order to realize the selectivity and bioavailability of platinum drugs to tumor cells,it is necessary to achieve the targeted drug delivery of platinum drugs.In this project,glucose,galactose,and mannose are used as transport substrates for the glucose transporter GLUT1.They are coupled to a platinum malonate complex through a glycosidic bond to form a leaving ligand.The chelating ligand is based on oxaliplatin and meso-cyclohexane diamine.The new glycoconjugate platinum complex can be recognized,bound and transported into cells by GLUT1,which can increase the solubility of platinum complexes while achieving targeted drug delivery.At the same time,Pt-DNA adducts with similar structures to oxaliplatin-DNA adducts could be formed,and the effect of chiral centers on molecular resistance was explored.A total of six new glycoconjugate platinum complexes were designed and synthesized in this project.All important intermediates and target products in the synthesis have been confirmed by ¹H NMR,¹³C NMR and HRMS.In the in vitro antitumor toxicity test,it targets human liver cancer cells（HepG2）,human melanoma cells（Mel-RM）,human colon cancer cells（HT29）,and oxaliplatin-resistant human colon cancer cells（HT29/oxa）.The results of 4 kinds of cells showed that by introducing sugar ligands in the molecule,the six kinds of glycoconjugate platinum complexes showed equal or even better antitumor activity than oxaliplatin,and had better targeted and no cross-resistance with cisplatin and carboplatin.The innovation of this subject is（1）a new sugar conjugated platinum（II）complex containing different sugar structures and diamine chelating ligands was synthesized through reasonable design by using the Warburg effect of tumors.The drug is designed to be a substrate of GLUT1 that can be actively recognized and absorbed by tumor cells,achieving drug targeting,water solubility and selectivity.（2）From the perspective of stereo chemistry,by changing the chiral center of oxaliplatin chelating ligand,it was found that the drug resistance coefficient of the compound has a great impact,which changed the drug resistance characteristics of oxaliplatin.In short,the novel glycoconjugate platinum complexes designed and synthesized in this subject successfully achieved the goals of good water solubility,good targeting,and no cross-resistance with cisplatin and carboplatin.