A Study Of Double Short-chain Polyethylene Glycol Prodrugs Of Rapamycin

Study on the prodrugs of rapamycin with double short-chain polyethylene glycol.The mOR inhibitor rapamycin is widely used in clinic as immunosuppressive drug after kidney transplantation.Clinical studies have found that rapamycin also has the effect of inhibiting tumor growth.But there exsist some problems like poor watersolubility and bioavailability,which disturb its development as anti-tumor drugs.PEG and m PEG are widely used in the modification of small molecule drugs,because of their characteristics of high water-solubility,good stability,low toxicity and none immunogenicity.They have achieved admirable results in improving the water solubility of small molecule anti-tumor drugs like irinotecan.According to our research,prodrugs of rapamycin with double short-chain polyethylene glycol can improve its water-solublity notablyAmino acids are often used to modify the anti-tumor drugs,for their good affinity and biocompatibility.Modification by amino acids and oligopeptides can improve its targeting on tumors and reduce its toxicity to normal cells.We select the moderate molecular-weight and water-soluble methoxypolyethylene glycol 500 to improve water-solubility by condensation between two free carboxyl of glutamic acid and hydroxy of methoxypolyethylene glycol 500.In order to improve the targeting on tumors,amino acids are introduced into the side chain,connecting with rapamycin on its 42 active hydroxyl through succinic acid or glutaric acid chain.Consequently,we have designed eight prodrugs of rapamycin with double short-chain polyethylene glycol.According to primary research,all of them have good water-solubility,and release rapamycin in vivo.Theoretical calculation of electronic circular dichroism of sporothriolide and determination of absolute configurationSporothriolide(6-hexyl-3-methylene tetrahydrofuran [3,4-b] furan-2,4-dione),firstly discovered from Sporothrix sp.(filamentous bacteria),is a kind of antifungal compound.It is a poly ketone compound,which is demonstrated by nuclear magnetic resonance(NMR)spectra.The chemical structure contains three chiral carbon centers and two possible relative configurations:(3a S,6R,6a R)and(3a R,6S,6a S).To confirm absolute configuration,time-dependent density functional theory(at MPW1LYP/6-31G(d,p)level)is used to calculate the electronic circular dichroism(ECD).By comparing the calculated and the experimental spectra,(3a S,6R,6a R)is identified.The right-and left-handed conformations of five membered rings lead to mirror symmetrical CDs,indicating the important influence of ring-flip of five membered ring on the CD.In addition,the intermolecular hydrogen bond between sporothriolide and solvent methanol leads to Cotton Effect shift less than 14.1 nm and enhancement of the peak intensity less than 75 cgs.It suggests that the solvation effect has little influence on the CD of sporothriolide.