A Facile One-Pot Synthesis of 7-Triethylsilylbaccatin III

Baloglu, Erkan; Miller, Michael L.; Cavanagh, Emily E.; Marien, Tracy; Roller, Elizabeth E.; Chari, Ravi

doi:10.1055/s-2005-863733

Cited by 6 publications

(2 citation statements)

References 2 publications

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“…Regioselective silylation of the C7 hydroxyl group [21,22] followed by purification and acetylation [22] afforded the 7-triethylsilyl-10-acetyl derivative 13. In our experience, silylations without purification of 12 [21] were inconsistent and usually gave mixtures from which 13 was difficult to isolate in pure form. The side chain on the 13α-hydroxyl group was then introduced by carbodiimide activation of excess enantio-pure N-t-butoxycarbonyl-protected oxazoline carboxylic acid 14 (2.5 equiv.)…”

Section: Substrates and Reagentsmentioning

confidence: 99%

Specificity of the N-benzoyl transferase responsible for the last step of Taxol biosynthesis

Long

Lagisetti

Coates

et al. 2008

Archives of Biochemistry and Biophysics

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The last few steps in the biosynthesis of the anticancer drug Taxol in yew (Taxus) species are thought to involve the attachment of β-phenylalanine to the C13-O-position of the advanced taxane diterpenoid intermediate baccatin III to yield N-debenzoyl-2′-deoxytaxol, followed by hydroxylation on the side chain at the C2′-position to afford N-debenzoyltaxol, and finally N-benzoylation to complete the pathway. A cDNA encoding the N-benzoyl transferase that catalyzes the terminal step of the reaction sequence was previously isolated from a family of transferase clones (derived from an induced Taxus cell cDNA library) by functional characterization of the corresponding recombinant enzyme using the available surrogate substrate N-debenzoyl-2′-deoxytaxol [Walker et al., Proc. Natl. Acad. Sci. USA 99 (2002) 9166-9171]. Semi-synthetic N-debenzoyltaxol was prepared by coupling of 7-triethylsilybaccatin III and (2R,3S)-β-phenylisoserine protected as the N-Boc N,O-isopropylidene derivative by means of carbodiimide activation and formic acid deprotections. The selectivity of the recombinant N-transferase for N-debenzoyltaxol was evaluated, and the enzyme was shown to prefer, by a catalytic efficiency factor of two, N-debenzoyltaxol over N-debenzoyl-2′-deoxytaxol as the taxoid co-substrate in the benzoyl transfer reaction, consistent with the assembly sequence involving 2′-hydroxylation prior to N-benzoylation. Selectivity for the acyl/ aroyl-CoA co-substrate was also examined, and the enzyme was shown to prefer benzoyl CoA. Transfer from tigloyl-CoA to N-debenzoyltaxol to afford cephalomannine (taxol B) was not observed, nor was transfer observed from hexanoyl-CoA or butanoyl-CoA to yield taxol C or taxol D, respectively. These results support the proposed sequence of reactions for C13-O-side chain assembly in Taxol biosynthesis, and suggest that other N-transferases are responsible for the formation of related, late pathway, N-acylated taxoids.

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Section: Substrates and Reagentsmentioning

confidence: 99%

Specificity of the N-benzoyl transferase responsible for the last step of Taxol biosynthesis

Long

Lagisetti

Coates

et al. 2008

Archives of Biochemistry and Biophysics

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“…β-Lactam 8 was then coupled with 7-(triethylsilyl)baccatin III33 under standard conditions to give the coupled product 9 . Hydrogenolysis of 9 followed by treatment with formic acid gave the aminodiol 10 , which was reacted with triphosgene to give the cyclic carbamate 11 .…”

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Synthesis and bioactivity of a side chain bridged paclitaxel: A test of the T-Taxol conformation

Hodge

Chen

Bane

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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A knowledge of the bioactive tubulin-binding conformation of paclitaxel (Taxol™) is crucial to a full understanding of the bioactivity of this important anticancer drug, and potentially also to the design of simplified analogs. The bioactive conformation has been shown to be best approximated by the T-Taxol conformation. As a further test of this conclusion, the paclitaxel analog 4 was designed as a compound which has all the chemical functionality necessary for activity, but which cannot adopt the T-Taxol conformation. The synthesis and bioassay of 4 confirmed its lack of activity, and thus provided further support for the T-Taxol conformation as the bioactive tubulin-binding conformation.The anticancer drug paclitaxel (1, Taxol™, PTX) is one of the most important anticancer natural products ever discovered, and has contributed significantly to human health. First reported from the Western yew, Taxus brevifolia, in1971, 1 it went through a long period of development, and was finally approved by the FDA for clinical use in 1992.A turning point in its development came with the discovery of its then unique mechanism of action as a promoter of the assembly of tubulin into microtubules. 2 The microtubule has been Correspondence to: David G. I. Kingston. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The normal functioning of tubulin assembly and disassembly is crucial to cell division, and any interference with this process disrupts cell division and leads to cell death by apoptosis. PTX owes its activity to its ability to bind to tubulin and suppress microtubule assembly dynamics. 3 Thus the nature of the binding of paclitaxel to tubulin, and in particular the tubulinbinding conformation of PTX, is an important question with potential applications in the design of improved taxoid drugs. NIH Public AccessSince PTX has a large flexible side chain at C13 and smaller flexible side chains at C2, C4, and C10, many different conformations are possible. Various proposals for the binding conformation have been made based on studies of the solution NMR spectra of PTX. NMR studies in nonpolar solvents suggested a "nonpolar" conformation, 6-8 while a "polar" conformation featuring hydrophobic interactions between the C2 benzoate, the C3′ phenyl group and the C4 acetate was proposed on the basis of NMR studies in polar solvents. 9-12 A third approach involved NMR studies using the NAMFIS deconvolution method, and this showed that PTX adopts 9-10 conformations in CDCl 3 . 13 An analysis of the electron crystallographic data in combination with the NAMFIS results suggested that t...

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