Pre-IND Evaluation Of Stable Derivatives Of CPS11

CPS11 significantly inhibited angiogenesis and tumor growth, both in vitro and in vivo. CPS11 can not be obtained with high purity and unstable during storage. Therefore, prodrugs of CPS11 are synthesized, and compound I and compoundⅡare chosen for efficacy study.CompoundⅡcan form salt with organic acid or inorganic acid. The stability of compoundⅡis significantly increased, and after one and half years the purity of compoundⅡis same as the initial purity. In pharmacokinetics study of compoundⅡ, after 1 min, only the active metabolite thalidomide and CPS11 could be detected following i.v. administration of compoundⅡ. CompoundⅡhas good bioavailability. The bioavailabilities in mice are 60.7% and 79.5% respectively after intragastric administration or intraperitoneal injection with CompondⅡ.In vitro, compoundⅡcan significantly inhibit ECV-304 cell growth, and the IC50 is 0.143μM. In Tube formation, significant inhibition is observed with CompoundⅡand the inhibition is 91.9%. In vivo, compoundⅡcould enhance antitumor efficacy of Taxol on MX-1 human breast cancer xenograft model, and the CDI is 0.4. CompoundⅡcan enhance antitumor efficacy of BCNU on G422 mouse glioma cancer model, and the CDI is 0.58. CompoundⅡcan significantly inhibit the metastasis of B16 murine melanoma and the inhibition is 74%.These results warrant further evaluation of compound I and compoundⅡas novel anti-cancer agents.