183133-94-0Relevant articles and documents
Design, synthesis and SAR study of Fluorine-containing 3rd-generation taxoids
Wang, Changwei,Chen, Lei,Sun, Yi,Guo, Wanrong,Taouil, Adam K.,Ojima, Iwao
, (2022/01/03)
It has been shown that the incorporation of fluorine or organofluorine groups into pharmaceutical and agricultural drugs often induces desirable pharmacological properties through unique protein-drug interactions involving fluorine. We have reported separately remarkable effects of the 2,2-difluorovinyl (DFV) group at the C3′ position, as well as those of the CF3O and CHF2O groups at the 3-position of the C2-benzoyl moiety of the 2nd- and 3rd-generation taxoids on their potency and pharmacological properties. Thus, it was very natural for us to investigate the combination of these two modifications in the 3rd-generation taxoids and to find out whether these two modifications are cooperative at the binding site in the β-tubulin or not, as well as to see how these effects are reflected in the biological activities of the new 3rd-generation DFV-taxoids. Accordingly, we designed, synthesized and fully characterized 14 new 3rd-generation DFV-taxoids. These new DFV-taxoids exhibited remarkable cytotoxicity against human breast, lung, colon, pancreatic and prostate cancer cell lines. All of these new DFV-taxoids exhibited subnanomolar IC50 values against drug-sensitive cell lines, A549, HT29, Vcap and PC3, as well as CFPAC-1. All of the novel DFV-taxoids exhibited 2–4 orders of magnitude greater potency against extremely drug-resistant cancer cell lines, LCC6-MDR and DLD-1, as compared to paclitaxel, indicating that these new DFV-taxoids can overcome MDR caused by the overexpression of Pgp and other ABC cassette transporters. Dose-response (kill) curve analysis of the new DFV-taxoids in LCC6-MDR and DLD-1 cell lines revealed highly impressive profiles of several new DFV-taxoids. The cooperative effects of the combination of the 3′-DFV group and 3-CF3O/CHF2O-benzoyl moiety at the C2 position were investigated in detail by molecular docking analysis. We found that both the 3′-DFV moiety and the 3-CF3O/3-CHF2O group of the C2-benzoate moiety are nicely accommodated to the deep hydrophobic pocket of the paclitaxel/taxoid binding site in the β-tubulin, enabling an enhanced binding mode through unique attractive interactions between fluorine/CF3O/CHF2O and the protein beyond those of paclitaxel and new-generation taxoids without bearing organofluorine groups, which are reflected in the remarkable potency of the new 3rd-generation DFV-taxoids.
Cabazitaxel precursor derivative as well as synthesis method and application thereof
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Paragraph 0080-0081, (2020/02/20)
The invention discloses a preparation method of 7,10-dimethoxy-10-DAB (deacetyl baccatin) and a cabazitaxel precursor derivative as well as a synthesis method and application of the cabazitaxel precursor derivative. The synthesis method disclosed by the invention has the advantages of being easy in raw material obtaining, less in step, simple and convenient in purification and high in yield, and has the prospect of industrial production. The cabazitaxel precursor derivative synthetisedby the synthesis methoddisclosed by the invention has excellent antitumor activity and great application prospects.
Method for synthesizing cabazitaxel by using 10-deacetylbaccatin III
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Paragraph 0017; 0021; 0025, (2018/06/23)
The invention discloses a method for synthesizing cabazitaxel by using 10-deacetylbaccatin III. The method comprises the steps of under the condition of existence of a solvent, a catalyst, and an anti-degradation agent, preparing a cabazitaxel intermediate 7,10-methoxy baccatin III by using 10-deacetylbaccatin III as a starting material; then, under the condition of existence of the catalyst and anti-degradation agent, performing a condensation reaction on the cabazitaxel intermediate 7,10-methoxy baccatin III and a side chain of docetaxel so as to prepare a cabazitaxel precursor N-1; performing hydrolyzation and ring opening on the cabazitaxel precursor N-1 under the acid condition, so as to obtain a crude cabazitaxel product; and performing column chromatography, crystallization, recrystallization and purification on the crude product so as to obtain the cabazitaxel. The method is low in cost and high in yield, the prepared product has high purity and contains fewer impurities, and the method is suitable for industrial production and promotion in the market.
Preparation method of 7beta,10beta-dimethoxy-10-deacetylbaccatin III
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, (2017/08/29)
The invention relates to a preparation method of 7beta,10beta-dimethoxy-10-deacetylbaccatin III. Particularly, the method provided by the invention takes acetylbaccatin as a raw material and comprises a series of the following steps: protecting through silicon protecting groups at a 7 site and a 13 site; selectively removing the silicon protecting group at the 7 site; directly alkylating at the 7 site and a 10 site; and finally, removing the silicon protecting group at the 13 site to prepare a taxane compound, namely the 7beta,10beta-dimethoxy-10-deacetylbaccatin III shown as a formula V. (The formula V is shown in the description.).
TAXANE COMPOUND, AND PREPARATION METHOD AND USE THEREOF
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, (2016/12/16)
Provided are taxanes compounds having the structure of formula I, preparation method thereof, and uses of compositions having the compound, pharmaceutical salts and solvates thereof as active ingredients in the preparation of oral antitumor drugs. In the formula, R1 is —COR6, —COOR6, and —CONR7aR7b; R2 is C1-C6 alkyl, C1-C6 alkenyl group, a substituted hydrocarbon group, a heterocyclic group, an aromatic group or a substituted aromatic group; R3 is —OR6, —OCOOR6, —OCOSR6, and —OCONR7aR7b; R4 is —OR6, —OCOOR6, —OCOSR6, —OCONR7aR7b, H, and OH; R6 is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl group, a substituted hydrocarbon group, an aromatic group or a heterocyclic group; and R7a and R7b are respectively hydrogen, a hydrocarbon group, a substituted hydrocarbon group or a heterocyclic group.
PROCESS FOR THE PREPARATION OF CABAZITAXEL AND ITS SOLVATES
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Page/Page column 14, (2015/06/25)
The present disclosure provides anisole and benzyl alcohol solvates of cabazitaxel and methods of their production. The solvates may be characterized by powder x-ray diffraction patterns. The present disclosure also provides methods for the synthesis of cabazitaxel.
NOVEL METHOD FOR PREPARING CABAZITAXEL FROM 10-DEACETYLBACCATIN III IN HIGH YIELD, AND NOVEL INTERMEDIATE THEREFOR
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, (2015/11/03)
The present invention relates to a novel method for preparing cabazitaxel from 10-deacetylbaccatin III, and a novel intermediate therefor, and more specifically, to: a method which allows cabazitaxel to be more easily prepared in a high yield and in a high purity within a short time compared with a conventional method by preparing cabazitaxel via a novel intermediate using 10-deacetylbaccatin III as a starting material, and thus is suitable for industrial mass production; and a novel intermediate therefor.
AMORPHOUS CABAZITAXEL
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Page/Page column 6, (2014/02/16)
The present invention is directed to an amorphous form of cabazitaxel, which can be prepared by dissolving a solid form of cabazitaxel in an organic solvent, and removing the organic solvent to dryness. The amorphous form of cabazitaxel is characterized by DSC as in FIG. 1 and/or X-ray powder diffraction pattern as in FIG. 2.
PROCESS FOR CABAZITAXEL
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Page/Page column 6, (2015/01/09)
The present invention provides an improved process for the preparation of 4α-acetoxy-2α-benzoyloxy-5β,20-epoxy-1β,13α-dihydroxy-7β,10β-dimethoxy-9-oxo-11-taxene (7β,10β-dimethoxy-10-deacetoxybaccatin III). The present invention also provides a novel process for the preparation of cabazitaxel.
The synthesis of novel taxoids for oral administration
Jing, Yun-Rong,Zhou, Wei,Li, Wan-Liang,Zhao, Lin-Xiang,Wang, Yong-Feng
, p. 194 - 203 (2014/01/17)
A group of novel taxoids, with modifications at C-7, C-10, C-3′ and C-14 positions of paclitaxel, was synthesized in order to improve their biological profile by decreasing their affinity with P-glycoprotein (P-gp) and increasing cellular permeability. Most of the new taxoids demonstrated the similar potent cytotoxic activities in MCF-7 human tumor cell line as paclitaxel in vitro. In the permeability assay with monolayers of Caco-2 cells, most of the compounds demonstrated an increased trans-cellular transport in A-to-B direction in comparison with paclitaxel. Among them the compounds T-13, T-15 and T-26 showed the highest permeability, and with efflux ratios better than that of ortataxel. The interaction of the compounds T-13 and T-26 with P-gp was evaluated using Madin-Darby canine kidney (MDCK)-multidrug resistance-1(MDR1) and MDCK-wild-type (WT). The results indicated that T-13 and T-26 were poor substrates for P-gp and possessed inhibiting effects of P-gp mediated efflux. It was thus clear that simultaneous modifications at the C-7, C-10 and C-3′ positions of paclitaxel significantly impaired its interactions with P-gp and interfered with P-gp mediated efflux.
