Study On The Stability And Antitumor Activity Of Camptothecin Ester Derivatives

Natural products and their derivatives are important sources of anti-cancer drugs.Camptothecin is a natural pentacyclic indole alkaloid with broad-spectrum antitumor activity extracted from a Chinese tree,Camptotheca acuminata Decne in 1966.But the practical use was limited due to its poor solubility,high toxicity and unstable active site.In our previous studies,series of CPT esterification derivatives were synthesized to improve water solubility and stability.In the present study,water solubility,stability and anti-tumor activity in vitro and in vivo of six camptothecin ester derivatives were evaluated,in order to provide basic data for their further application.(1)In this study,the solubility of six esterification derivatives of camptothecin in water was determined.Compared with CPT,the water-solubility of six camptothecin esterification derivatives was significantly improved.The water solubility of tboc-CPT-Gly-Ile was the lowest,and the solubility of tboc-CPT-Gly-Val and tboc-CPT-Gly-Gly among the other five derivatives was the highest,and the water solubility of CPT was more than doubled.(2)A simple HPLC method with fluorescence detection was established for the determination of six camptothecin ester derivatives,and the linearity,precision,accuracy,and stability of the method were all within an acceptable range.The results showed that the stability was the best in PBS(pH 6.8),and 6 compounds degraded less than 50%within 72 hours;the second was the stability in PBS(pH 7.4)and most compounds degraded about 60%within 72 hours.The stability is the worst in HCl(pH 1.2),and nearly 80%of all the comounds degraded within in 72 hours.Compared with PBS,all these six compounds are also not very stable in plasma,and degraded more than 80%within 72 hours.(3)To elucidate the potential activity of these camptothecin ester derivatives,we tested its antitumor activity against five cancer cell lines,including human pancreatic cancer cell line MPC2,human colon cancer cell line HT29,human prostate carcinoma cell line DU 145,human lung squamous cell carcinoma cell line NCI H520 and human ovarian cancer cell line 27742774(human ovarian cancer cell line),compared with CPT and HCPT.The results showed that the antitumor activities of the 6 camptothecin ester derivatives were all lower than that of CPT,while tboc-CPT-Gly-Gly and tboc-CPT-Gly-Phe showed stronger activity than that of HCPT.(4)To elucidate the in vivo anti-cancer activity of tboc-CPT-Gly-Gly and tboc-CPT-Gly-Phe,Hepatoma 22(H22)cells were transplanted into the ICR mice.CPT and CPT-11 was used as positive control.The result shows that the in vivo anti-cancer activities of tboc-CPT-Gly-Gly and tboc-CPT-Gly-Phe were as well as CPT-11.The mice treated with CPT were all dead,while the mice of other three treatments all survived;these results indicated that CPT is more toxic.There was no significant difference in body weight for all the groups,indicating that these compouns had no obvious toxicity.