Synthesis of Natural Ecteinascidins (ET-729, ET-745, ET-759B, ET-736, ET-637, ET-594) from Cyanosafracin B

Menchaca, Roberto; Martínez, Valentín Alejandro; Rodríguez, Alberto; Rodriguez, Natividad; Flores, Marcelo; Gallego, Pilar; Manzanares, Ignacio; Cuevas, Carmen

doi:10.1021/jo034547i

Cited by 73 publications

(40 citation statements)

References 53 publications

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“…Oxidation of 1b with m-chloroperbenzoic acid (m-CPBA) in dichloromethane gave ecteinascidin 786 (1c) in 92% yield. 16) Treatment of 1c with acetic anhydride in pyridine afforded 2c in 78% yield. Compound 2a was obtained by reacting 2b with AgNO 3 in 41% yield, along with the recovery of 2b in 46% yield.…”

Section: Resultsmentioning

confidence: 99%

Chemistry of Ecteinascidins. Part 2. Preparation of 6'-O-Acyl Derivatives of Stable Ecteinascidin and Evaluation of Cytotoxicity

Puthongking

Patarapanich

Amnuoypol

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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Ecteinascidin 743 (1a)2) is an exceedingly potent and rare marine-derived antitumor compound isolated from the Caribbean tunicate Ecteinascidia turbinata, 3) and is currently being studied in phase II/III clinical trials for ovarian, breast, endometrial, prostate, and pediatric cancers.4) Its novel structure, combined with meager availability from nature and unique mechanism of action, has made 1a a very attractive and important synthetic target. The first complete synthetic route to 1a was accomplished by Corey and coworkers, 5,6) and this strategy has subsequently enabled its large-scale preparation. 7,8) In addition, two independent groups, Fukuyama et al. 9) and Zhu et al.,10) were able to design synthetic routes to 1a. Ecteinascidin 743 is the first of a new class of DNA binding agents having a complex transcriptiontargeted mechanism of action. Although the detailed molecular mechanism of action remains unclear, 1a was reported to induce the DNA-sequence-selective alkylation of guanine N2 in a minor groove of duplex DNA. 11) Interestingly, the C-subunit, which is perpendicular to the combined AB-subunit, is responsible for the propeller-like character of pentacyclic natural products, such as saframycins and renieramycins, 12) both of which are fairly flat molecules. It was postulated that this bending structure of 1a disrupts DNA-protein binding and may be responsible for the enhanced biological activities of ecteinascidins. 13,14) We succeeded in isolating the stable ecteinascidin 770 (1b) along with ecteinascidin 786 (1c) from the Thai tunicate, Ecteinascidia thurstoni, which was pretreated with potassium cyanide in buffer solution.1) The availability of 1b enabled us to prepare ecteinascidin analogs having increased antitumor activity and broadened spectrum. In this work, we focused on the conversion of 1b into corresponding aromatic ester derivatives 3-19 along with diacetates 2a-c. Results and DiscussionAccording to the procedure for the acetylation of 1a to the corresponding acetate in a published patent, 15) we treated 1b with acetic anhydride in pyridine to give 2b in 82% yield (Fig. 1). Oxidation of 1b with m-chloroperbenzoic acid (m-CPBA) in dichloromethane gave ecteinascidin 786 (1c) in 92% yield.16) Treatment of 1c with acetic anhydride in pyridine afforded 2c in 78% yield. Compound 2a was obtained by reacting 2b with AgNO 3 in 41% yield, along with the recovery of 2b in 46% yield. In the primary screening for in vitro cytotoxicity, three human solid tumor cell lines (HCT116 colon carcinoma, QG56 lung carcinoma, and DU145 prostate carcinoma) were used. As shown in Table 1, diacetyl derivatives 2a-c possessed low cytotoxicity relative to 1b. Oxidation of the sulfide group of ecteinascidins resulted in dramatically diminished cytotoxicity.Next, we examined the transformation of 1b into the corresponding aromatic ester derivatives. In contrast with the acetylation of 1b as above, treatment of 1b with benzoyl chloride and a catalytic amount of 4-dimethylaminopyridine (DMAP) in pyridine afforded mai...

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Section: Resultsmentioning

confidence: 99%

Chemistry of Ecteinascidins. Part 2. Preparation of 6'-O-Acyl Derivatives of Stable Ecteinascidin and Evaluation of Cytotoxicity

Puthongking

Patarapanich

Amnuoypol

et al. 2006

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…63 They are broad-spectrum antitumor agents that are several orders of magnitude more potent than other tetrahydroisoquinoline alkaloids. The first one to be developed was trabectedin (ecteinascidin 743, ET-743, Yondelis ® ), which was originally isolated from the marine tunicate Ecteinascidia turbinata and obtained by mariculture techniques during the first stages of clinical development, but which it is now produced by semisynthesis from safracin B.…”

Section: Figure 615mentioning

confidence: 99%

Anticancer Drugs That Interact with the DNA Minor Groove

Avendaño

Menéndez²

2015

Medicinal Chemistry of Anticancer Drugs

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“…Thus, the synthesis and biological evaluation of Pt 650 2 was first reported by Corey et al [13][14][15][16] and exhibited similar biological activity to the natural product. A semi-synthetic route was achieved by Cuevas et al [17,18] through fermentation of the bacteria Pseudomonas fluorescens to produce cyanosafracin B (3) [19], an antibiotic of bacterial origin. However, since the discovery of Pt 650, several research groups were involved in the research of potentially more active structures, bearing a piperazine system [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of (±)-phthalascidin 622

et al. 2010

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A synthesis of functionalized phenolic-amino-alcohols (±)-8 and (±)-16 as synthetic precursors of the catechol tetrahydroisoquinoline structure of phthalascidin 650 was disclosed. (±)-8 was prepared in 5 steps from the commercially available sesamol. Starting from 3-methyl catechol 5, 8 steps gave rise to the synthesis of phenolic-amino-alcohol (±)-16 in 27% overall yield. This synthetic strategy involved the elaboration of fully functionalized aromatic aldehyde 13 and its transformation into a phenolic -amino-alcohol (±)-16, through a Knoevenagel condensation, simultaneous reduction of nitroketene and ester functions, and hydrogenolysis of the benzyl protecting group. The pentacycle (±)-4 was obtained after 4 additional steps. The Pictet-Spengler cyclisation between the phenolic-amino-alcohol (±)-16 and the N-protected -amino-aldehyde 4 allowed to obtain (1,3′)-bis-tetrahydroisoquinoline 17 with N-methylated and N-Fmoc removed. The last step was a Swern oxidation allowing the expected intramolecular condensation. phthalascidin, ecteinascidin, (1,3′)-bis-tetrahydroisoquinoline, Pictet-Spengler, Bishler-Napieralsky

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Synthesis of Natural Ecteinascidins (ET-729, ET-745, ET-759B, ET-736, ET-637, ET-594) from Cyanosafracin B

Cited by 73 publications

References 53 publications

Chemistry of Ecteinascidins. Part 2. Preparation of 6'-O-Acyl Derivatives of Stable Ecteinascidin and Evaluation of Cytotoxicity

Chemistry of Ecteinascidins. Part 2. Preparation of 6'-O-Acyl Derivatives of Stable Ecteinascidin and Evaluation of Cytotoxicity

Anticancer Drugs That Interact with the DNA Minor Groove

Synthesis of (±)-phthalascidin 622

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