Total Synthesis of a Conformationally Constrained Didemnin B Analog

Xiao, Dong; Vera, _; Liang, Bo; Mm, Joullié

doi:10.1021/jo001640n

Cited by 24 publications

(10 citation statements)

References 38 publications

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“…Cys189 also controls the multimerization of CTR1 (Eisses and Kaplan, 2002;Lee et al, 2007;Sinani et al, 2007). The relative binding affinities are such that the C-terminal end of CTR1 can transfer copper to ATOX1 and presumably also to copper chaperone for superoxide dismutase and cytochrome c oxidase assembly homolog (Xiao et al, 2001), although binding of ATOX1 to CTR1 has not actually been demonstrated.…”

Section: Structure and Copper Transport Function Of Ctr1mentioning

confidence: 99%

Copper Transporters and the Cellular Pharmacology of the Platinum-Containing Cancer Drugs

Howell¹,

Safaei²,

Larson³

et al. 2010

Mol Pharmacol

298

243

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Multiple lines of evidence indicate that the platinum-containing cancer drugs enter cells, are distributed to various subcellular compartments, and are exported from cells via transporters that evolved to manage copper homeostasis. The cytotoxicity of the platinum drugs is directly related to how much drug enters the cell, and almost all cells that have acquired resistance to the platinum drugs exhibit reduced drug accumulation. The major copper influx transporter, copper transporter 1 (CTR1), has now been shown to control the tumor cell accumulation and cytotoxic effect of cisplatin, carboplatin, and oxaliplatin. There is a good correlation between change in CTR1 expression and acquired cisplatin resistance among ovarian cancer cell lines, and genetic knockout of CTR1 renders cells resistant to cisplatin in vivo. The expression of CTR1 is regulated at the transcriptional level by copper via Sp1 and at the post-translational level by the proteosome. Copper and cisplatin both trigger the down-regulation of CTR1 via a process that involves ubiquitination and proteosomal degradation and requires the copper chaperone antioxidant protein 1 (ATOX1). The cisplatin-induced degradation of CTR1 can be blocked with the proteosome inhibitor bortezomib, and this increases the cellular uptake and the cytotoxicity of cisplatin in a synergistic manner. Copper and platinum(II) have similar sulfur binding characteristics, and the presence of stacked rings of methionines and cysteines in the CTR1 trimer suggest a mechanism by which CTR1 selectively transports copper and the platinum-containing drugs via sequential transchelation reactions similar to the manner in which copper is passed from ATOX1 to the copper efflux transporters.

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Section: Structure and Copper Transport Function Of Ctr1mentioning

confidence: 99%

Copper Transporters and the Cellular Pharmacology of the Platinum-Containing Cancer Drugs

Howell¹,

Safaei²,

Larson³

et al. 2010

Mol Pharmacol

298

243

View full text Add to dashboard Cite

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“…The group later synthesized another conformationally constrained analogue, in which the isostatine moiety was replaced by a (S,S,S)-b-hydroxyg-aminocyclohexanecarboxylic acid, to probe the biological conformation of didemnin B. 78 The constrained analogue (11) was tested for protein biosynthesis inhibition and showed about 20-fold decrease in activity, compared to didemnin B.…”

Section: Modifications In the Hip-isostatine Regionmentioning

confidence: 99%

Didemnins, tamandarins and related natural products

et al. 2012

Self Cite

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Since the discovery and isolation of the didemnin family of marine depsipeptides in 1981, the synthesis and biological activity of its congeners have been of great interest to the scientific community. The didemnins have demonstrated antitumor, antiviral, and immunosuppressive activity at low nano- and femtomolar levels. Of the congeners, didemnin B was the first marine natural product to reach phase II clinical trials in the United States, stimulating many analogue syntheses to date. About two decades later, tamandarins A and B were isolated, and were found to possess very similar structure and biological activity to that of the didemnin B. These compounds have shown impressive biological activity and some progress has been made in establishing structure-activity relationships. However, their molecular mechanism of action still remains unclear. This review highlights the long-standing study of didemnins and its critical application towards the understanding of the molecular mechanism of action of tamandarins and their potential use as therapeutic agents.

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“…Joullié and co-workers reported the synthesis of chiral cyclohexane carboxylic acid 7 (R = H) by a Diels-Alder reaction between camphor sultam derived acrylic acid derivative 8 and 1-acetoxy-1,3-butadiene ( 9) under two conditions: toluene reflux and 5M LiClO 4 in Et 2 O at room temperature. 7 We examined both conditions and found that separation of the isomers obtained under the toluene reflux conditions was difficult on a larger scale, while the Diels-Alder reaction in 5M LiClO 4 in Et 2 O was very slow (the reaction had not completed even after 8 days), although the diastereoselectivity was very high as reported. We thus abandoned the Diels-Alder reaction between 8 and 9 in this study.…”

Section: Letter Syn Lettmentioning

confidence: 77%

Concise Stereocontrolled Synthesis of an α-Carbagalactose Segment of RCAI-56, a Candidate Anticancer Agent

Ushida

Nagai

Adachi

et al. 2019

Synlett

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Total Synthesis of a Conformationally Constrained Didemnin B Analog

Abstract: The total synthesis of a didemnin B analogue containing a conformationally constrained replacement for the isostatine moiety is reported. Synthetic highlights include an improved preparation of 2-hydroxy-3-cyclohexenecarboxylic acid and a new strategy for accessing the macrocycle.

Cited by 24 publications

References 38 publications

Copper Transporters and the Cellular Pharmacology of the Platinum-Containing Cancer Drugs

Copper Transporters and the Cellular Pharmacology of the Platinum-Containing Cancer Drugs

Didemnins, tamandarins and related natural products

Concise Stereocontrolled Synthesis of an α-Carbagalactose Segment of RCAI-56, a Candidate Anticancer Agent

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