On Biocatalysis as Resourceful Methodology for Complex Syntheses: Selective Catalysis, Cascades and Biosynthesis
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
The small biosynthetic amounts of anti-cancer agent paclitaxel (25, taxol) obtained from the Pacific yew (Taxus brevifolia) led to the development of alternative production strategies (Patel, 1998). Although total syntheses were published, these were not economically justifiable due to the complexity of the molecule. Since an intermediate of the taxol biosynthesis, 10-deacetylbaccatin III (28), occurs in larger amounts in the leaves of the European yew (Taxus baccata), Holton (1993) developed a semisynthesis approach for the production of taxol (25). Starting from 10-deacetylbaccatin III (28), the 7-O-triethylsilyl baccatin III (29) is first obtained by two consecutive protection reactions, which resulted after conversion with the Ojima lactone (30) and a subsequent deprotection in taxol (Fig. 21.11).
Role of Nanoparticles in Cancer Immunotherapy
D. Sakthi Kumar, Aswathy Ravindran Girija in Bionanotechnology in Cancer, 2023
MDSCs inhibit T cells-based immune responses. Lee et al. have shown the use of baccatin III (a precursor of paclitaxel) in reducing the infiltration of MDSC at tumor site [78]. Jeanbart et al. conjugated 6-thioguanine to polyethylene glycol(PEG)-PPS polymer micelles that efficiently depleted MDSCs and finally resulted in reduced tumor burden [79]. In another exciting report, Wang et al. have developed poly(amidoamine) dendrimers for ‘all-trans retinoic acids (ATRA)’ delivery that enhances the myeloid cells differentiation into mature DCs, macrophages, and granulocytes [80, 81].
Biotechnological Production of Prenylated Xanthones for Pharmaceutical Use
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
A recent review by Sperl and Sieber (2018) provides information on the current status and advancements made in this field. Recently, a representative example of cascade biocatalysis toward taxol production (Fig. 4.9; generic name paclitaxel) was studied (Thornburg et al., 2017). Taxol is a Food and Drug Administration (FDA) approved microtubule-stabilizing chemotherapeutic drug used for the treatment of different types of cancer (Panchagnula, 1998; Priyadarshini and Aparajitha, 2012; Weaver, 2014; Kampan et al., 2015). In a 200 μl one-pot reaction, a four-step enzymatic cascade reaction was developed, utilizing Rhodopseudomonas palustris benzoate-CoA ligase (RpBZL; England et al., 1995), a modified non-ribosomal peptide synthase from Bacillus brevis, a Taxus plant phenylpropanoyltransferase and a benzoyltransferase. The cascade produced 230 ng of the anticancerous analogue N-debenzoyl-N-(2-furoryl)-paclitaxel and its precursor N-debenzoylpaclitaxel from the commercially available intermediate baccatin III (Fig. 4.9). This multienzyme reaction network shows great prospective for scale-up and is a promising tool for regioselective N- and O-acylation steps, evading tricky protecting group manipulations (Thornburg et al., 2017). Similarly, one-pot synthesis of xanthone analogues can be achieved via a multienzyme cascade approach involving BZL (Singh et al., unpublished) and the rest enzymes of the biosynthetic sequence (BPS, CYPs, and aPTs; Fig. 4.3). Chemical structures of taxol and its precursor baccatin III, which was used in cascade biocatalysis to form N-debenzoyl-N-(2-furoryl)-paclitaxel and its intermediate N-debenzoylpaclitaxel.
Characterization of metabolites of larotaxel in rat by liquid chromatography coupled with Q exactive high-resolution benchtop quadrupole orbitrap mass spectrometer
Published in Xenobiotica, 2018
Zhenzhen Liu, Pengyi Hou, Lian Liu, Feng Qian
Paclitaxel and docetaxel are the two main taxanes in clinical use with success for patients with ovarian, breast or lung cancer, which have contributed significantly to the improved treatment of a number of neoplastic diseases (Ahn et al., 2014; Karavasilis et al., 2014; Martin et al., 2005; Tolaney et al., 2015). However, over time multiple drug mechanism of resistance becomes a major obstacle to the successful treatment of malignancies, with the induction of the efflux pump P-glycoprotein (P-gp) being one of the most important features (Metzger-Filho et al., 2009). Larotaxel (XRP9881, RPR109881), prepared by synthesis of 10-desacetyl baccatin-III, is a novel anti-cancer agent with low affinity for P-gp (Metzger-Filho et al., 2009; Pivot et al., 2008). Larotaxel had a broad spectrum of activity against both the docetaxel-sensitive and docetaxel-resistant or paclitaxel-resistant cell lines such as B16 melanoma, C38 colon adenocarcinoma, 13/C breast adenocarcinoma, P03 pancreatic ductal adenocarcinoma and P388 leukemia (Kurata et al., 2000; Pivot et al., 2008).
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