Synthesis And Study Of Monodisperse Oligoethylene Glycols Modified Propofol And Camptothecin Prodrugs

Polyethylene glycols(PEGs)have been widely used in the pharmaceutical industry due to its good water solubility and biocompatibility.PEGylation of drug molecules can improve solubility and stability,reduce dosing frequency and immunogenicity,and prolong blood circulation.However,the polydispersity of regular PEGs has slowed the development and production of related drugs over a long period of time.Modification of drugs with regular PEGs results difficulties in purification,characterization,quality control,and clinic application.Fortunately,these problems could be avoided by replacing regular PEGs with monodisperse PEGs(M-PEGs).In our group's previous studies,a highly efficient method for M-PEGs was development based on the nucleophilic ring-opening reaction of macrocyclic sulfate.On this basis,we further explored the application of modification of small molecule drugs with M-PEGs,including Propofol,Camptothecin and its analogues.Propofol is one of the most widely used intravenous anesthetic in clinical practice.Comparing to other anesthetics,Propofol has many advantages,such as rapid onset,rapid recovery,and rapid elimination.Because of its poor water solubility,the traditional way is to formulate Propofol as a fat emulsion in clinical application,which brings a range of problems,such as injection pain,poor physical stability,prone to bacterial infection,disorder of patient's fat metabolism with long-term use.Therefore,we design and synthesis 3 types of Propofol prodrugs with M-PEGs modification,including acetals(5a-5f),carbonates(7a-7f),and esters(9a-9f).Through evaluation the physicochemical property,biocompatibility,anesthetic effect and drug release profile in plasma of Propofol prodrugs,esters 9e and 9f were identified as promising anesthetic in clinical practice.Camptothecin(CPT)and 10-Hydroxycamptothecin(HCPT)are natural products isolated from the plant Camptotheca acuminata,which kill cancer cells through binding to topoisomerase I and DNA complex and causing DNA damage,show high anticancer activity.However,their low water solubility and short in vivo half time severely limited their clinic application.To address these issues,we design and synthesis a number of CPT,HCPT and SN38 prodrugs with M-PEGs modification,including HCPT-ethers(11a-11i),HCPT-carbonates(13a-13j),CPT-carbonates(14a-14j)and SN38-carbonates(15a,15b).Through evaluation the physicochemical property,anti-tumor efficacy and drug release profile in plasma of these prodrugs,HCPT-carbonates(13a-13j),CPT-carbonates(14a-14j)and SN38-carbonates(15a,15b)with good solubility,cytotoxicity,and valuable drug release profile were identified as promising anticancer drug candidates.