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Upstream product

• 740802-74-8 (3R,4S)-1-(4-methoxyphenyl)-3-acetoxy-4-(2-methyl-1-propenyl)azetidin-2-one 
• 201044-87-3 (3R,4S)-3-Hydroxy-1-(4-methoxy-phenyl)-4-(2-methyl-propenyl)-azetidin-2-one 
• 178250-07-2 (3R,4S)-1-(4-methoxyphenyl)-3-triisopropylsiloxy-4-(2-methylprop-1-enyl)azetidin-2-one 
• 1895-39-2 sodium chlorodifluoroacetate 
• 245657-85-6 (3R,4R)-1-(4-methoxyphenyl)-3-triisopropylsiloxy-4-formylazetidin-2-one 
• 450336-25-1 [(triisopropylsilyl)oxy]acetic acid 
• 192758-34-2 benzyl (triisopropylsilyloxy)acetate 
• 75-61-6 dibromodifluoromethane 

Relevant academic research and scientific papers

Design, synthesis and SAR study of Fluorine-containing 3rd-generation taxoids

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.

Fluorinated taxane compound, preparation method therefor and application of fluorinated taxane compound

The invention discloses a fluorinated taxane compound, a preparation method therefor and an application of the fluorinated taxane compound. The compound has a structural general formula represented bya formula I. Proven by pharmacological experiments, compared with paclitaxel, a series of fluorinated taxane derivatives synthesized by the method have cytotoxicity superior to that of the paclitaxelto a multidrug-resistant human mammary cancer cell line MCF-7/Adr and an ovarian cancer cell line NCI/Adr and represent cytotoxicity superior to that of the paclitaxel to a colon cancer cell line HCT-116 with overexpressed neoplasm stem cells.

Synthesis and biological evaluation of novel 3′-difluorovinyl taxoids

A series of 3′-difluorovinyl taxoids with C10 modifications, as well as those with C2 and C10 modifications, were strategically designed to block the metabolism by cytochrome P-450 3A4 enzyme and synthesized. These novel difluorovinyl taxoids were evaluated for their cytotoxicity against drug-sensitive human breast (MCF7), multidrug-resistant (MDR) human ovarian (NCI/ADR), human colon (HT-29) and human pancreatic (PANC-1) cancer cell lines. 3′-Difluorovinyl taxoids exhibit several to 16 times better activity against MCF7, HT-29 and PANC-1 cell lines and up to three orders of magnitude higher potency against NCI/ADR cell line as compared to paclitaxel. Structure-activity relationship study shows the critical importance of the C2 modifications on the activity against MDR cancer cell line, while the C10 modifications have a rather minor effect on the potency with some exceptions. The effect of the C2 modifications on potency against MCF7 cell line increases in the following order: H 3. Among the twenty five 3′-difluorovinyl taxoids evaluated, eight taxoids exhibited less than 100 pM IC50 values against MCF7 cell line. Difluorovinyl taxoids induced GTP-independent tubulin polymerization much faster than paclitaxel. Then, the resulting microtubules were stable to Ca2+-induced depolymerization, indicating strong stabilization of microtubules. Molecular modeling study indicated that a difluorovinyl taxoid binds to β-tubulin in a manner that is consistent with the REDOR-Taxol structure. The difluorovinyl group appears to mimic the isobutenyl group to some extent, but with very different electronic property, which may account for the unique activities of difluorovinyl taxoids.

FLUOROTAXOID-FATTY ACID CONJUGATES AND PHARMACEUTICAL COMPOSITIONS THEREOF

The invention relates to fluorotaxoid-fatty acid conjugates and pharmaceutical compositions thereof. The conjugates have the following formula:

FLUOROTAXOIDS

The invention relates to fluorinated second generation taxoid compounds, pharmaceutical formulations thereof, and their use for inhibiting the growth of cancer cells in a mammal.