We report herein eleven 2′-N-acyl derivatives that were prepared from ecteinascidin 770 (Et 770: 1b) via 18,6′-O-bisallyl protected compound (4) in excellent yields. 2′-N-Acyl derivatives (6a-k) generally showed higher cytotoxicity than 1b. Among them, 3-quinolineacyl derivative (6g) and 4-fluorocinnamoyl derivative (6h) exhibited approximately 50-and 70-fold higher cytotoxicity to the HCT116 human colon carcinoma cell line, respectively, than 1b. Both compounds are potent inhibitors of the in vitro growth of several tumor cells and are therefore promising leads for further optimization. We also report the transformation of 1b into Et 788 (3), which is the first example of an ecteinascidin derivative having a primary amide at C-21 position.Key words ecteinascidin; marine natural product; structure-activity relationship study; transformation; cytotoxicity Members of the tetrahydroisoquinoline family of natural products have persistently attracted considerable interest for more than 30 years due to their novel structures and meager availability in nature, as well as their potent antitumor activity 1,2) ( Fig. 1). Of particular significance is ecteinascidin 743 (Et 743, 1a), which has received plentiful attention for its strong in vivo antitumor activity.3,4) It is marketed in over fifty countries for the treatment of soft-tissue sarcoma, and phase II/III clinical trials for the treatment of other cancers are ongoing. 5,6) Unfortunately, compared with the many structureactivity relationship (SAR) studies of related natural products, such as saframycins and renieramycins, 7-15) SAR studies of ecteinascidins have been limited because of their meager amounts and the low chemical diversity of their biosynthetically produced derivatives.
16)As part of our search for new metabolites via the isolation and characterization of biologically active compounds from Thai marine invertebrates, we isolated ecteinascidin 770 (Et 770: 1b) in gram scale from the Thai tunicate Ecteinascidia thurstoni by pretreatment with potassium cyanide in buffer solution. We also elucidated the structures of 1b and its sulfoxide, Et 786 (2).17) The availability of 1b enabled us to prepare several ecteinascidin derivatives possessing improved cytotoxicity profiles. We previously reported the preparation of 6′-O-acyl derivatives of 1b and established their cytotoxicity in several human tumor cell lines. 18) We found that the nitrogen-containing heterocyclic ester derivatives showed similar in vitro cytotoxicity to 1b, whereas the other derivatives were less cytotoxic than 1b. We also reported a three-step transformation of 1b into 2′-N-acyl derivative 6 via 18,6′-O-bisallyl protected derivative 4 and determined the in vitro cytotoxicity of 6 by measuring IC 50 values in HCT 116 human colon carcinoma, QG56 human lung carcinoma, and DU145 human prostate carcinoma cell lines. 19) In this paper, we report the preparation of eleven additional 2′-N-acyl derivatives from 1b via 4, most of which exhibited higher cytotoxicity than parent 1b and the previousl...