Chemical structure modification of anticancer Ecteinnascidin Alcaloids from the Thai tunicate Ecteinascidia Thurstoni

Abstract

Ecteinascidin 743 (Et 743; 1), a member of the tristetrahydroisoquinoline alkaloids previously isolated from the tunicate, Ecteinascidia turbinata, is a potent anticancer agent and is currently undergoing in phase II/III clinical trials. Et 770 (2) and Et 786 (4), two anticancer agents from the Thai tunicate, E. thurstoni, were efficiently isolated with the KCN pretreated process. Three diacetate esters of Ets 743, 770, and 786 (18-20) were prepared and the acetylation was reacted to the phenolic hydroxyls at C-18 and C-6' of the ecteinascidins. Seventeen acyl esters were prepared on the phenolic hydroxyl at C-6' of Et 770 with the corresponding acid anhydrides or acid chlorides or acids in the presence of N,N-dicyclohexylcarbodiimide (DCC) as the coupling reagent to yield the monoacyl derivatives (21-37). In contrast, the reaction of indole-3-carboxylic acid with Et 770 in the presence of DCC provided the amide derivative 39, which was substituted at N-2' of the C-subunit. The synthesized derivatives were evaluated for cytotoxicity against HCT116 (human colon carcinoma), QG56 (human lung carcinoma), and DU145 (human prostate carcinoma) and exhibited excellent cytotoxic activities at nanomolar concentration. The cytotoxic data supported that the cyano or the hydroxy groups at C-21 position are essential for the cytotoxic activity. Moreover, oxidation of the sulfide bridge of ecteinascidins resulted in dramatically diminished activity. Most benzoyl ester derivatives exhibited dramatically decreased cytotoxicity while 4"-nitrobenzoyl (22) and 4"- methoxybenzoyl (28) ester derivatives as well as the N-containing heterocyclic ester derivatives (30-31 and 34-37) possessed cytotoxicity similar to the precursor (2). Interestingly, only the indole-3-carbonyl amide derivative (39) exhibited higher cytotoxicity than the parent compound (2). The selective N-demethylation with cerium (IV) ammonium nitrate (CAN) was worked on the structural models containing the ABC ring system, which included the A-subunit of Ets. The optimal condition was achieved in 5 equimolars of CAN in the presence of aqeous-acetonitrile. However, this investigation revealed that the protection at the phenolic hydroxyl and the transformation of cyanoamine to amide carbonyl group are the key steps for the oxidative N-demethylation using CAN for those model compounds.