Ecteinascidins

Model studies directed toward the synthesis of Ecteinascidin 743 employed an elegant Pictet-Spengler cyclization of phenethylamine 54 and the 1,2-dicarbonyl compound 55 to assemble the spiro tetrahydroisoquinoline 56 in a stereospecific fashion. " The silica-catalyzed condensation reaction provided 56 in excellent yield. 

DNA alkylation has the potential to yield a time-dependent spectrum of adducts, in which initially formed kinetically favored lesions give way to the thermodynamically favored adducts over time. Reversible alkylation has been observed at several of the nucleophilic sites in DNA, including N3A (CC-1065,7, Scheme 8.10, duocarmycin, 8)," " NIA (qui-none methide, 9)," N7G (leinamycin, Schane 8.11, aflatoxin Bj epoxide, 10 and quinone methide, 9),57.ii4.ii8 (quinone methide, 9)," and bPG (ecteinascidin 743,11)." The bidentate Nl/ISPG adduct of malondialdehyde also forms reversibly. ... 

Zewail-Foote, M. Hurley, L. H. Differential rates of reversibility of ecteinascidin 743-DNA covalent adducts from different sequences lead to migration to favored bonding sites. J. Am. Chem. Soc. 2001, 123, 6485-6495. 

Ecteinascidin 743 (Et-743) is a complex natural product, which also seems to work by trapping DNA-binding proteins at sites where structural distortion of the DNA is recognized. The chemical structures of Cisplatin and Et-743 are shown earlier in this review. 

Hurley LH, Zewail-Foote, M (2001) The antitumor agent ecteinascidin 743 characterization of its covalent DNA adducts and chemical stability. Adv Exp Med Biol 500 289-299 Inche AG, La Thangue NB (2006) Chromatin control and cancer-drug discovery reaUzing the promise. 

Zewail-Foote M, Hurley LH (1999) Ecteinascidin 743 a minor groove alkylator that bends DNA toward the major groove. J Med Chem 42 2493-2497... 

Trabectedin (36 Yondelis, ecteinascidin-743, ET-743 Zelfia and Johnson and Johnson, 2007), a tetrahydroisoquinoline alkaloid produced hy the ascidian Ecteinascidia turbinate,received approval for its sale in Europe, Russia and South Korea by Zelfia and Johnson and Johnson under the brand name YondelisT for the treatment of advanced soft tissue sarcoma (STS). Trabectedin (36) binds to the minor groove of DNA and inhibits cell proliferation by disrupting the cell cycle. 

Pommier Y, Kohlagen G BaiUy C, Waring M, Mazumder A, Kohn K. (1996) DNA sequence- and structure-selective alkylation of guanine N2 in the DNA minor groove by ecteinascidin 743, a potent antitumor compound from the Caribbean tunicate Ecteinascidia turbinata. Biochemistry 35 13303-13309. 

Sakai R, Rinehart KL, Guan Y, Wang AH. (1992) Additional antitumor ecteinascidins from a Caribbean tunicate Crystal structures and activities in vivo. Proc Natl Acad Sci USA 89 11456-11460. 

Sakai R, Jares-Erijman EA, Manzanares I, Elipe MVS, Rinehart KL. (1996) Ecteinascidins Putative biosynthetic precursors and absolute stereochemistry. J Am Chem Soc 118 9017-9023. 

Soares DG Escargueil AE, Poindessous V, Sarasin A, de Gramont A, Bonatto D, Henriques JA, Larsen AK. (2007) Replication and homologous recombination repair regulate DNA double-strand break formation by the antitumor alkylator ecteinascidin 743. Proc Natl Acad Sci USA 104 13062-13067. 

Cuevas C, Perez M, Martm MJ, Chicharro JL, Femandez-Rivas C, Flores M, Francesch A, GaUego P, Zarzuelo M, de La Calle F, Garcia J, Polanco C, Rodriguez I, Manzanares I. (2000) Synthesis of ecteinascidin ET-743 and phthalascidin PT-650 from cyanosafracin. B Org Lett 2 2545-2548. 

Isocyanide-based MCR was also applied for the total synthesis studies of natural products containing piperazine substructure. For example, trabectedin (also known as ecteinascidin 743 or ET-743) is undergoing clinical trials for the treatment of breast, prostate, and pediatric sarcomas. Ecteinascidin 743 (2) is an extremely potent antitumor agent isolated from a marine tunicate, Ecteinascidia turbinate [12]. Eukuyama et al. developed the total synthesis of ecteinascidin 743 from a Ugi reaction [13]. The reaction of p-methoxyphenyl isocyanide 3 gave Ugi product 7, which was cyclized to DKP intermediate 8 (Scheme 1). 

Scheme 1 Ugi reaction as a central step in the total synthesis of Ecteinascidin 743 by Fukuyama et al.

Rinehart KL, Holt TG, Fiegeau NL, Stroh JG, Keifer PA, Sun F, Li LH, Martin DG (2002) Ecteinascidins 729, 743, 745, 759A, 759B, and 770 potent antitumor agents from the Caribbean tunicate Ecteinascidia turbinata. J Org Chem 55(15) 4512-4515... 

Martinez, E.J. Corey, E.J. (2000) A new, more efficioit, and effective process for the synthesis of a key pentacyclic intomediate fen- production of ecteinascidin and phtfaalascidin antitumor agents. Org. Lett., 2, 993-6. 

Seaman, F.C. Hurley, L.H. (1998) Molecular basis for the DNA sequence selectivity of ecteinascidin 736 and 743 evidence for the dominant role of direct readout via hydrogen bonding. J. Am. Chem. Soc., 120, 13028-41. 

The in vivo antitumour activity of extracts of the tunicate Ecteinascidia turbinata was noted in the late 1960s [152] but the active metabolites were only isolated and identified much later by two research groups. These complex alkaloids were termed the ecteinascidins and are... 

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