PREPARATION AND CYTOTOXICITY OF ECTEINASCIDIN 770 DERIVATIVES FROM THE THAI TUNICATE ECTEINASCIDIA THURSTONI

Abstract

Ecteinascidin 743 (Et 743), a tris-tetrahydroisoquinoline alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, has been approved by European Medicines Agency as a new anticancer drug for the patients with soft tissue sarcoma and relapsed ovarian cancer. The stabilized ecteinascidin 770 (Et 770) was recently isolated in large yield from the Thai tunicate E. thurstoni by pretreatment with potassium cyanide. To improve the cytotoxicity of Et 770, the chemical modification has been particularly focused at the 2'-N position on the C-subunit of Et 770. Nine new 2'-N-acyl Et 770 derivatives were prepared from Et 770 via the intermediate 18,6'-O-bisallyl Et 770 in acceptable yields. The synthesized derivatives were evaluated for cytotoxicity against three human solid carcinoma cell lines, including colorectal carcinoma (HCT116), human lung carcinoma (QG56), and human prostate carcinoma (DU145) cell lines and exhibited excellent cytotoxicity with IC50 at nanomolar concentrations. Among them, 2'-N-(4''-fluorocinnamoyl) Et 770 displayed the most potent cytotoxicity with approximately 70-fold higher potency to HCT116 than the parent Et 770. Therefore, this new derivative is a promising lead for further development as a new anticancer agent.