The Constituent of the Heartwood of Taxus cuspidata Sieb. et Zucc.

Miyazaki, Masaru; Shimizu, Kazumasa; Mishima, Hiroshi; Kurabayashi, Masaaki

doi:10.1248/cpb.16.546

Cited by 32 publications

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“…For this purpose, taxusin (the tetraacetate of taxa-4(20),11(12)-dien-5a,9a,10b,13a-tetraol) was employed as a surrogate substrate to test microsomal preparations and to functionally evaluate the extant cytochrome P450 clones for taxoid C1, C2 and C7 hydroxylase activities, and for the presumed C4,C20-epoxidase. (+)-Taxusin ( Figure 6) is a prominent metabolite of yew heartwood (Miyazaki et al, 1968;Della Casa de Marcano and Halsall, 1969) in which it is considered a dead-end metabolite, not a possible intermediate in Taxol formation (Floss and Mocek, 1995). Nevertheless, the natural occurrence in Taxus of a broad range of taxusin-like metabolites bearing additional oxygen functional groups at C1, C2 or C7 (Baloglu and Kingston, 1999) encouraged the use of this material as an alternate substrate for testing microsomal oxygenase activities and for screening cytochrome P450 clones in yeast.…”

Section: Cytochrome P450 Taxoid Oxygenasesmentioning

confidence: 99%

Taxol Biosynthesis and Molecular Genetics

et al. 2006

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Biosynthesis of the anticancer drug Taxol in Taxus (yew) species involves 19 steps from the universal diterpenoid progenitor geranylgeranyl diphosphate derived by the plastidial methyl erythritol phosphate pathway for isoprenoid precursor supply. Following the committed cyclization to the taxane skeleton, eight cytochrome P450-mediated oxygenations, three CoA-dependent acyl/aroyl transfers, an oxidation at C9, and oxetane (D-ring) formation yield the intermediate baccatin III, to which the functionally important C13-side chain is appended in five additional steps. To gain further insight about Taxol biosynthesis relevant to the improved production of this drug, and to draw inferences about the organization, regulation, and origins of this complex natural product pathway, Taxus suspension cells (induced for taxoid biosynthesis by methyl jasmonate) were used for feeding studies, as the foundation for cell-free enzymology and as the source of transcripts for cDNA library construction and a variety of cloning strategies. This approach has led to the elucidation of early and late pathway segments, the isolation and characterization of over half of the pathway enzymes and their corresponding genes, and the identification of candidate cDNAs for the remaining pathway steps, and it has provided many promising targets for genetically engineering more efficient biosynthetic production of Taxol and its precursors.

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Section: Cytochrome P450 Taxoid Oxygenasesmentioning

confidence: 99%

Taxol Biosynthesis and Molecular Genetics

et al. 2006

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“…As illustrated in Figure 1, Taxol™ can be viewed as a "level 11" taxane due to the presence of 9 oxidized carbon atoms and two degrees of unsaturation; over 100 natural products at this oxidation state have been isolated. Similarly, decinnamoyltaxinine E ( 2 ) 29 , taxabaccatin III ( 3 ) 30 , taxusin ( 4 ) 31–36 , taxuyunnanine D ( 5 ) 37,38 , and taxadiene ( 6 ) 39–41 can be viewed as level 3–5 taxanes and represent over 100 additional natural products. In this report, the first enantioselective total syntheses of decinnamoyltaxinine E ( 2 ) and taxabaccatin III ( 3 ) are presented.…”

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confidence: 99%

Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes

et al. 2016

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In the realm of natural product chemistry, few isolates have risen to the level of fame justifiably accorded to Taxol™ (1) and its chemical siblings. This report describes the most concise route to date for accessing the highly oxidized members of this family. As representative members of taxanes containing five oxygen atoms, decinnamoyltaxinine E (2) and taxabaccatin III (3) have succumbed to enantioselective total synthesis for the first time in only 18 steps from a simple olefin starting material. The route to these natural products is enabled by a strategy that holistically mimics Nature's approach (two-phase synthesis) and features a carefully choreographed sequence of stereoselective oxidations and a remarkable redox-isomerization to set the key trans-diol present in 2 and 3. This work lays the critical groundwork necessary to access even higher oxidized taxanes such as 1 in a more practical fashion thus empowering a medicinal chemistry campaign that is not wedded to semi-synthesis.

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“…Investigations into further oxygenation steps including positions C1, C2, and C7 have proven to be more difficult in terms of the order and nature of occurring intermediates . Most studies use taxusin (highly abundant), as a surrogate substrate to evaluate the hydroxylase activities of cytochrome P450s for C1, C2, and C7 positions. , In 2004, taxoid-2α-hydroxylase and taxoid-7β-hydroxylase were isolated and characterized by Chau and Croteau. , Both efficiently oxidized the C2 and C7 positions of taxusin ( 19 ), and further studies in Taxus microsomes indicated a possible 7β-hydroxylation–2α-hydroxylation sequence, to yield 8 . To the best of our knowledge, the 1β-hydroxylase is still unidentified, but metabolite accumulation studies indicate C1 oxygenation to take place at the final stage …”

Section: Biogenetic Origin and Relationship Of Classical And Nonclass...mentioning

confidence: 99%

The Chemistry of Nonclassical Taxane Diterpene

et al. 2021

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The taxane diterpenes are a pharmaceutically vital family of natural products, consisting of more than 550 congeners. All taxane diterpenes are isolated from slow growing evergreen shrubs (genus Taxus) commonly known as "yews" and have a history of over 50 years as potent anticancer compounds. The most prominent congener, taxol (paclitaxel = PTX), has been used in clinics for more than 25 years and is one of the top-selling anticancer drugs worldwide, with annual sales reaching 1.5 billion USD in 1999. Within the taxane diterpene family 11 different scaffolds originating from rearrangements, fragmentations, or transannular C−C bond formations of the "classical taxane core" are known. Among them, five different scaffolds alone belong to the so-called complex or cyclotaxane subfamily, their signature structural feature bearing different types and numbers of transannular C−C bonds across the classical taxane backbone. For synthetic chemists, these five scaffolds represent by far the most challenging of all and have thus evaded total synthesis as well as detailed pharmaceutical evaluationthe latter due to extremely poor sourcing from natural producers. The cousinship of complex taxanes to taxol renders them potentially interesting compounds for drug research in the fight against cancer. This Account specifically summarizes the work on nonclassical taxanes from a biosynthetic, as well as a synthetic, point and provides a synthetic perspective on complex taxanes. Special attention is given to the biosynthetic relationship of complex taxanes and their biological emergence from classical taxanes. The transannular C−C bond forming events in the biosynthesis leading to the five individual scaffolds within this subfamily are structured on the basis of the exact type and number of these specific C−C bond formations. Since functionalization of the classical taxane core in the "oxidase phase" of the biosynthesis precedes the formation of complex taxanes, and is in part prerequisite for these transannular cyclization events, a detailed discussion of these oxidations of the classical taxane backbone is provided. Synthetic efforts toward nonclassical taxanes are scarce in literature and are thus presented in a comprehensive manner for abeotaxanes and complex taxanes. The last part of this Account deals with a synthetic perspective on the synthesis of complex taxanes (cyclotaxanes) and how these most intricate scaffolds can potentially be obtained via a deconvolution strategy. This discussion involves in part unpublished results by our group and is based upon synthetic studies in the literature. The deconvolution strategy we advocate aims for selective fragmentations of the signature transannular C−C bonds of the most intricate scaffold represented by the natural product canataxpropellane, which has recently been synthesized by our group. This strategy represents the converse process of the biosynthesis of complex taxanes (e.g., transannular cyclizations) and is enabled and feasible due to our approach to the canataxpropellane sc...

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The Constituent of the Heartwood of Taxus cuspidata Sieb. et Zucc.

Cited by 32 publications

References 0 publications

Taxol Biosynthesis and Molecular Genetics

Taxol Biosynthesis and Molecular Genetics

Short, Enantioselective Total Synthesis of Highly Oxidized Taxanes

The Chemistry of Nonclassical Taxane Diterpene

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