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Cabazitaxel

Basic information Antitumour Activity Pharmacokinetics Safety Related Supplier
Cabazitaxel Basic information
Cabazitaxel Chemical Properties
  • Melting point:180 °C
  • Boiling point:870.7±65.0 °C(Predicted)
  • Density 1.31
  • form White solid.
  • pka11.20±0.46(Predicted)
Safety Information
  • Safety Statements 24/25
  • HS Code 29329990
Cabazitaxel Usage And Synthesis
  • Antitumour Activity

    Cabazitaxel is a semisynthetic taxane derivative that acts as a microtubule inhibitor. It binds to tubulin, promoting the assembly of tubulin into microtubules and inhibiting their disassembly, which results in microtubule stabilization, the inhibition of cell division, cell cycle arrest and the arrest of tumour proliferation. Cabazitaxel demonstrated antitumour activity against advanced human tumours xenografted in mice. As well as being active in docetaxel-sensitive tumours, cabazitaxel showed activity in tumour models insensitive to chemotherapy, including docetaxel. Cabazitaxel also penetrates the blood-brain barrier to a greater extent than docetaxel.

  • Pharmacokinetics

    The pharmacokinetic data for cabazitaxel demonstrated dose proportionality, with a high plasma clearance and a long terminal half-life. The very large volume of distribution at steady state suggests extensive penetration into tissues. Of interest, cabazitaxel is able to cross the blood-brain barrier in preclinical models. Cabazitaxel is mainly metabolized by the cytochrome P450 (CYP) enzyme 3A4/5 and to a lesser extent by CYP2C8, suggesting that it has the potential to inhibit CYP3A enzymes.

  • DescriptionIn June 2010, the U.S. FDA approved cabazitaxel (also referred to as XRP6258 and RPR 116258A) in combination with the steroid prednisone for the treatment of metastatic Castration-Resistant Prostate Cancer (mCRPC) for patients who were previously treated with a docetaxelcontaining regimen for late-stage disease.
    Cabazitaxel is a semisynthetic analog of the natural product taxol, which is isolated from the bark of the yew tree. Cabazitaxel is a microtubule inhibitor that binds to the taxol-binding site of tubulin. Similar to other tubulin inhibitors of the taxol class, cabazitaxel inhibits microtubule disassembly resulting in mitotic blockade and cell death. Docetaxel, also a semisynthetic taxol analog, was approved by the FDA for the treatment of mCRPC in 2004. However, docetaxel is a substrate for P-gp, which is thought to contribute to the constitutive and acquired resistance of cancer cells to taxanes. Cabazitaxel has poor affinity for P-gp and showed antitumor activity in preclinical in vitro studies and in vivo tumor models that overexpress this protein. Cabazitaxel is synthesized on a commercial scale from 10-deacetylbaccatin .
  • Chemical PropertiesWhite solid
  • OriginatorSanofi-Aventis (France)
  • UsesCabazitaxel (Jevtana, XRP6258) is a semi-synthetic derivative of a natural taxoid.
  • UsesA novel semi-synthetic taxane with antitumor activity used for the treatment of castration-resistant prostate cancer. A microtubule inhibitor.
  • DefinitionChEBI: A tetracyclic diterpenoid that is 10-deacetylbaccatin III having O-methyl groups attached at positions 7 and 10 as well as an O-(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hy roxy-3-phenylpropanoyl group attached at position 13. Acts as a microtubule inhibitor, binds tubulin and promotes microtubule assembly and simultaneously inhibits disassembly.
  • brand nameJevtana
  • Clinical UseCabazitaxel was developed by Sanofi-Aventis as an intravenous injectable drug for the treatment of hormone-refractory metastatic prostate cancer. As a microtubule inhibitor, cabazitaxel differs from docetaxel because it exhibits a much weaker affinity for P-glycoprotein (P-gp), an adenosine triphosphate (ATP)-dependent drug efflux pump. Cancer cells that express P-gp become resistant to taxanes, and the effectiveness of docetaxel can be limited by its high substrate affinity for P-gp. Clinical studies confirmed that cabazitaxel retains activity in docetaxel-resistant tumors. Common adverse events with cabazitaxel include diarrhea and neutropenia. Cabazitaxel in combination with prednisone is an important new treatment option for men with docetaxel-refractory metastatic CRPC (castration-resistant prostate cancer).
  • Chemical SynthesisThe semi-synthesis of cabazitaxel started from 10- deacetylbaccatin III (15) which can be prepared from 7-xylosyl-10-deacetylbaccatin natural product mixture according to a literature process procedure (the Scheme). 10-Deacetylbaccatin III was protected with triethylsilyl chloride (TESCl) in pyridine to afford the corresponding 7,13-bis-silyl ether in 51% yield, which was methylated with MeI and NaH in DMF to give 10-methoxy-7,13-bis silyl ether 16 in 76% yield. After de-silylation of 16 with triethylamine trihydrofluoride complex at room temperature, triol 17 was obtained in 77% yield. Selective methylation of 17 with MeI and NaH in DMF at 0 oC provided 7,10-dimethyl ether 18 in 74% yield. Compound 18 was condensed with commercially available oxazolidinecarboxylic acid 19 in the presence of dicyclohexylcarbodiimide/dimethylaminopyridine (DCC/DMAP) in ethyl acetate at room temperature to generate ester 20 in 76% yield. The oxazolidine moiety of compound 20 was selectively hydrolyzed under mild acidic conditions to yield the hydroxy Boc-amino ester derivative cabazitaxel (III) in 32% yield.

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