Antitumor tetrahydroisoquinoline alkaloids from the colonial ascidian Ecteinascidia turbinata

Wright, Amy E.; Forleo, Dorilyn A.; Gunawardana, Geewananda P.; Gunasekera, Sarath P.; Koehn, Frank E.; McConnell, Oliver J.

doi:10.1021/jo00302a006

Cited by 255 publications

(134 citation statements)

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“…Ecteinascidin 743 (Et 743) is an exceedingly potent antitumor agent isolated from extracts of the marine tunicate Ecteinascidia turbinate that is currently undergoing phase II clinical trials as a result of its promising efficacy in preclinical antitumor tests (1)(2)(3)(4)(5). Although the detailed molecular mechanism of action still remains unclear, Et 743 has been reported to yield DNA sequence-selective alkylation of guanine N2 in the minor groove of duplex DNA (6).…”

mentioning

confidence: 99%

Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743

Martínez

Owa

Schreiber

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

166

102

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A series of totally synthetic molecules that are structurally related to the marine natural product ecteinascidin 743 (Et 743) has been prepared and evaluated as antitumor agents. The most active of these, phthalascidin, is very similar to Et 743 with regard to in vitro potency and mode of action across a variety of cell types. The antiproliferative activity of phthalascidin (IC 50 ‫؍‬ 0.1-1 nM) is greater than that of the agents Taxol, camptothecin, adriamycin, mitomycin C, cisplatin, bleomycin, and etoposide by 1-3 orders of magnitude, and the mechanism of action is clearly different from these currently used drugs. Phthalascidin and Et 743 induce DNA-protein cross-linking and, although they seem to interact with topoisomerase (topo) I (but not topo II), topo I may not be the primary protein target of these agents. Phthalascidin and Et 743 show undiminished potency in camptothecin-and etoposide-resistant cells. Phthalascidin is more readily synthesized and more stable than Et 743, which is currently undergoing clinical trials. The relationship of chemical structure and antitumor activity for this class of molecules has been clarified by this study.Ecteinascidin 743 (Et 743) is an exceedingly potent antitumor agent isolated from extracts of the marine tunicate Ecteinascidia turbinate that is currently undergoing phase II clinical trials as a result of its promising efficacy in preclinical antitumor tests (1-5). Although the detailed molecular mechanism of action still remains unclear, Et 743 has been reported to yield DNA sequence-selective alkylation of guanine N2 in the minor groove of duplex DNA (6). Additionally, bioassays for antimetabolic activities and enzyme inhibitions revealed Et 743 showed potent inhibition of DNA and RNA synthesis and of RNA polymerase activity but much less inhibition of DNA polymerase activity (7). Despite the minute human dosage of Et 743 currently being used in the clinic, Ϸ2 mg per person by i.v. infusion, the supply of this rare natural product is inadequate for large-scale studies. Consequently, a multistep total chemical synthesis has been developed to provide the amounts of Et 743 required for medical use (8). The availability of this synthetic process and the desirability of finding simpler and more stable structural relatives of Et 743 has led us to synthesize and evaluate new members of this class of substances. Described herein is the discovery of a number of compounds that significantly exhibit antitumor activity. The most potent of these, phthalascidin (Pt 650, Fig. 1

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mentioning

confidence: 99%

Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743

Martínez

Owa

Schreiber

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

166

102

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“…Structure elucidation of the active components of the extracts was achieved in 1990, where it was shown that ecteinascidin-743 had the highest potency (Wright et al 1990;Rinehart et al 1990). Soon after the structures were available, the total synthesis was achieved (Corey et al 1996;Martinez and Corey 2000), and a semisynthetic approach that used the antibacterial natural product cyanosafractin (Cuevas et al 2000).…”

Section: Ecteinascidin-743mentioning

confidence: 99%

Sources for Leads: Natural Products and Libraries

Herwerden

Süssmuth

2015

New Approaches to Drug Discovery

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Natural products have traditionally been a major source of leads in the drug discovery process. However, the development of high-throughput screening led to an increased interest in synthetic methods that enabled the rapid construction of large libraries of molecules. This resulted in the termination or downscaling of many natural product research programs, but the chemical libraries did not necessarily produce a larger amount of drug leads. On one hand, this chapter explores the current state of natural product research within the drug discovery process. On the other hand it evaluates the efforts made to increase the amount of leads generated from chemical libraries and considers what role natural products could play here.

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“…The lead compound, trabectedin (ET-743, 84), is regarded as a successful story of modern marine drug research: it is indeed the first representative of a marine natural product to receive marketing authorization for the treatment of patients with advanced or metastatic soft tissue sarcomas (STS) and relapsed platinum-sensitive ovarian cancer under the brand name Yondelis (87), and ET 770 (88), was reported by the Rinehart group in 1990, of which ET-743 was the most abundant representative [67]. Simultaneously, Wright and co-workers described compounds 83 and 84 [68], but the unequivocal assignment of the absolute stereochemistry was achieved only when the X-ray crystal structures of the natural N…”

Section: Tetrahydroisoquinoline Alkaloids: Ecteinascidins a New Clasmentioning

confidence: 99%

Alkaloids from Marine Invertebrates as Important Leads for Anticancer Drugs Discovery and Development

et al. 2014

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Abstract:The present review describes research on novel natural antitumor alkaloids isolated from marine invertebrates. The structure, origin, and confirmed cytotoxic activity of more than 130 novel alkaloids belonging to several structural families (indoles, pyrroles, pyrazines, quinolines, and pyridoacridines), together with some of their synthetic analogs, are illustrated. Recent discoveries concerning the current state of the potential and/or development of some of them as new drugs, as well as the current knowledge regarding their modes of action, are also summarized. A special emphasis is given to the role of marine invertebrate alkaloids as an important source of leads for anticancer drug discovery.

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Antitumor tetrahydroisoquinoline alkaloids from the colonial ascidian Ecteinascidia turbinata

Cited by 255 publications

References 2 publications

Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743

Phthalascidin, a synthetic antitumor agent with potency and mode of action comparable to ecteinascidin 743

Sources for Leads: Natural Products and Libraries

Alkaloids from Marine Invertebrates as Important Leads for Anticancer Drugs Discovery and Development

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