Stereocontrolled total synthesis of (+)-vincristine

Kuboyama, Takeshi; Yokoshima, Satoshi; Tokuyama, Hidetoshi; Fukuyama, Tohru

doi:10.1073/pnas.0401323101

Cited by 95 publications

(54 citation statements)

References 25 publications

(34 reference statements)

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“…Many MIAs and MIA derivatives have medicinal properties; for example, vinblastine, vincristine, and vinflunine are approved anticancer therapeutics (4,5). These structurally complex compounds can be difficult to chemically synthesize (6,7). Consequently, industrial production relies on extraction from the plant, but these compounds are often produced in small quantities as complex mixtures, making isolation challenging, laborious, and expensive (8)(9)(10).…”

mentioning

confidence: 99%

De novo production of the plant-derived alkaloid strictosidine in yeast

Brown

Clastre

Courdavault

et al. 2015

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

391

347

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The monoterpene indole alkaloids are a large group of plant-derived specialized metabolites, many of which have valuable pharmaceutical or biological activity. There are ∼3,000 monoterpene indole alkaloids produced by thousands of plant species in numerous families. The diverse chemical structures found in this metabolite class originate from strictosidine, which is the last common biosynthetic intermediate for all monoterpene indole alkaloid enzymatic pathways. Reconstitution of biosynthetic pathways in a heterologous host is a promising strategy for rapid and inexpensive production of complex molecules that are found in plants. Here, we demonstrate how strictosidine can be produced de novo in a Saccharomyces cerevisiae host from 14 known monoterpene indole alkaloid pathway genes, along with an additional seven genes and three gene deletions that enhance secondary metabolism. This system provides an important resource for developing the production of more complex plantderived alkaloids, engineering of nonnatural derivatives, identification of bottlenecks in monoterpene indole alkaloid biosynthesis, and discovery of new pathway genes in a convenient yeast host.

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mentioning

confidence: 99%

De novo production of the plant-derived alkaloid strictosidine in yeast

Brown

Clastre

Courdavault

et al. 2015

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

391

347

View full text Add to dashboard Cite

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“…We experienced the same problem and came to the conclusion that this degradation product is vincristine itself (Damen et al, 2009a). When vinblastine oxidizes, vincristine is formed (Kuboyama et al, 2004; see also structures A and B in Fig. 1).…”

Section: Internal Standardsmentioning

confidence: 80%

High‐performance liquid chromatography coupled with mass spectrometry for the quantitative analysis of vinca‐alkaloids in biological matrices: a concise survey from the literature

Damen

Rosing

Schellens

et al. 2009

Biomedical Chromatography

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The bioanalysis of vinca-alkaloids has been investigated extensively. High-performance liquid chromatography coupled to ultraviolet, fluorescence or electrochemical detection have been described. During recent years liquid chromatography coupled with mass spectrometry (LC-MS) has become the first choice for the quantitative bioanalysis of the vinca anticancer agents. This paper reviews recent methods for the bio-analysis of vinca-alkaloids using LC-MS, supplemented with our own experience. We will focus on sample pre-treatment, chromatography and MS detection and pay attention to problems which can occur during the bioanalysis of vinca-alkaloids. These problems encounter carry-over and absorption effects and solutions will be provided how to circumvent these problems.

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“…When vinblastine oxidizes, vincristine is formed. 37 We tested different batches of vinblastine from different manufacturers and all contained some vincristine. For this reason vinblastine is not a suitable internal standard for vincristine when using an ultra-sensitive LC/MS/MS system.…”

Section: Chromatographymentioning

confidence: 99%

Validated assay for the simultaneous quantification of total vincristine and actinomycin‐D concentrations in human EDTA plasma and of vincristine concentrations in human plasma ultrafiltrate by high‐performance liquid chromatography coupled with tandem mass spectrometry

Damen

Israëls

Caron

et al. 2009

Rapid Comm Mass Spectrometry

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A sensitive, specific and efficient high-performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS) assay for the simultaneous determination of total vincristine and actinomycin-D concentrations in human plasma and an assay for the determination of unbound vincristine are presented. Electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI) and heated electrospray ionization (H-ESI) were tested as ionization interfaces. For reasons of robustness ESI was chosen followed by tandem mass spectrometry (ESI-MS/MS). For the plasma assay a 30 microL aliquot was protein precipitated with acetonitrile/methanol (50:50, v/v) containing the internal standard vinorelbine and 10 microL volumes were injected onto the HPLC system. To determine unbound vincristine, ultrafiltrate was produced from plasma using 30 kDa centrifugal filter units. The plasma ultrafiltrate was mixed with methanol (50:50, v/v), internal standard vinorelbine was added and 20 microL aliquots were injected onto the HPLC system. Separation was achieved on a 50x2.1 mm i.d. Xbridge C18 column using 1 mM ammonium acetate/acetonitrile (30:70, v/v) adjusted to pH 10.5 with ammonia, run in a gradient with methanol at a flow rate of 0.4 mL/min. HPLC run time was 6 min. The assay quantifies in plasma vincristine from 0.25 to 100 ng/mL and actinomycin-D from 0.5 to 250 ng/mL using plasma sample volumes of only 30 microL. Vincristine in plasma ultrafiltrate can be quantified from 1 to 100 ng/mL. Validation results demonstrate that vincristine and actinomycin-D can be accurately and precisely quantified in human plasma and plasma ultrafiltrate with the presented methods. The assays are now in use to support clinical pharmacological studies in children treated with vincristine and actinomycin-D.

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Stereocontrolled total synthesis of (+)-vincristine

Cited by 95 publications

References 25 publications

De novo production of the plant-derived alkaloid strictosidine in yeast

De novo production of the plant-derived alkaloid strictosidine in yeast

High‐performance liquid chromatography coupled with mass spectrometry for the quantitative analysis of vinca‐alkaloids in biological matrices: a concise survey from the literature

Validated assay for the simultaneous quantification of total vincristine and actinomycin‐D concentrations in human EDTA plasma and of vincristine concentrations in human plasma ultrafiltrate by high‐performance liquid chromatography coupled with tandem mass spectrometry

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