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Two-Phase Synthesis of Taxol.

ABSTRACT: Taxol (a brand name for paclitaxel) is widely regarded as among the most famed natural isolates ever discovered, and has been the subject of innumerable studies in both basic and applied science. Its documented success as an anticancer agent, coupled with early concerns over supply, stimulated a furious worldwide effort from chemists to provide a solution for its preparation through total synthesis. Those pioneering studies proved the feasibility of retrosynthetically guided access to synthetic Taxol, albeit in minute quantities and with enormous effort. In practice, all medicinal chemistry efforts and eventual commercialization have relied upon natural (plant material) or biosynthetically derived (synthetic biology) supplies. Here we show how a complementary divergent synthetic approach that is holistically patterned off of biosynthetic machinery for terpene synthesis can be used to arrive at Taxol.

SUBMITTER: Kanda Y

PROVIDER: S-EPMC8349513 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Design and synthesis of simplified taxol analogs based on the T-Taxol bioactive conformation.

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Sensitization of breast cancer cells to taxol by inhibition of taxol resistance gene 1.

Project description:The purpose of this study was to determine the role of taxol resistance gene 1 (TXR1) in a taxol-resistant breast cancer cell line. Expression levels of TXR1 and thrombospondin-1 (TSP1) were detected by RT-PCR and Western blot analysis. In MCF-7 cells transfected with TXR1 plasmids, the expression of a number of drug resistance genes was monitored, as well as cell proliferation. MCF-7 cells were also transiently transfected with a chemically synthesized small interfering RNA (siRNA) targeting TXR1. Taxol concentrations varying from 0.6 to 6 μg/ml were shown to inhibit the proliferation of MCF-7 cells in a time- and dose-dependent manner by arresting cells in the G2/M phase. Additionally, 0.06 μg/ml taxol was used to establish a taxol-resistant MCF-7 cell line, MCF-7/T. When TXR1 was exogenously expressed, a taxol-resistant phenotype was further induced and the expression levels of BCRP, GSTP1 and MVP increased. Transient transfection of TXR1-targeting siRNAs was shown to restore the chemosensitivity of MCF-7 cells. These results suggest that an increased expression of TXR1 is a novel mechanism for reversing the taxol resistance of breast cancer cells.

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Project description:Taxol is one of the most potent and effective anticancer drugs and is originally isolated from Taxus species. To investigate the specific regulatory mechanisms of taxol synthesis in Taxus wallichiana var. mairei, RNA-seq was conducted to reveal the differences in transcriptional levels between wild type (WT) and "Jinxishan" (JXS), a cultivar selected from a population of Taxus mairei that shows about 3-fold higher taxol content in the needles than WT. Our results indicated that high expressions of the genes taxadienol acetyltransferase (TAT), taxadiene 5-alpha hydroxylase (T5H), 5-alpha-taxadienol-10-beta-hydroxylase (T10OH), and 2-debenzoyl-7,13-diacetylbaccatin III-2-O-benzoyl-transferase (DBBT), which catalyze a series of key acetylation and hydroxylation steps, are the main cause of high taxol content in JXS. Moreover, in the present study, the activation of jasmonic acid (JA) signal transduction and its crosstalk with gibberellin (GA), auxin, and ethylene (ET) explained the elevation of differentially expressed genes (DEGs) from the taxol biosynthesis pathway. This also indicates that taxol biosynthesis in T. mairei is associated with the balance of cell development and defense. TF-encoding (transcriptional factor) genes, represented by the ethylene-responsive transcription factor (ERF), basic/helix-loop-helix (bHLH), MYB, and WRKY families, were detected as differentially expressed between JXS and WT, further indicating that the regulation of hormone signaling on taxol biosynthesis genes was mediated by transcription factors (TFs). To our knowledge, this is the first study to illustrate the regulatory mechanisms of taxol synthesis in a new cultivar of T. mairei with a high taxol content in its needles. These transcriptome data provide reasonable explanations for the variation of taxol content between WT and JXS.

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Transcription profiling of mouse lymphoma L5178Y cells treated with Taxol (Paclitaxel) ILSI-HESI Genotoxicity Study - Taxol

Project description:Mouse lymphoma L5178Y cells are treated with Taxol (Paclitaxel) [CAS:33069-62-4;CHEBI:7887] and harvested at 4 and 24 hours for analysis.

2004-02-13 | E-TOXM-9 | biostudies-arrayexpress

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