183133-96-2 Usage
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.
Description
In 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 Properties
White solid
Originator
Sanofi-Aventis (France)
Uses
Different sources of media describe the Uses of 183133-96-2 differently. You can refer to the following data:
1. Cabazitaxel (Jevtana, XRP6258) is a semi-synthetic derivative of a natural taxoid.
2. A novel semi-synthetic taxane with antitumor activity used for the treatment of castration-resistant prostate cancer. A microtubule inhibitor.
Definition
ChEBI: 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 name
Jevtana
Clinical Use
Cabazitaxel 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).
Synthesis
The 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.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: Avoid with clarithromycin, rifabutin,
rifampicin and telithromycin.
Antidepressants: Avoid with St John's wort.
Antiepileptics: Avoid with carbamazepine,
fosphenytoin, phenobarbital, phenytoin and
primidone.
Antifungals: Avoid with itraconazole, ketoconazole
and voriconazole.
Antipsychotics: Avoid with clozapine (increased risk
of agranulocytosis).
Antivirals: Avoid with atazanavir, indinavir, ritonavir
and saquinavir.
Metabolism
Extensively metabolised in the liver (>95%), mainly by
the CYP3A4 isoenzyme (80-90%). Cabazitaxel is the
main circulating compound in human plasma. Seven
metabolites were detected in plasma (including 3 active
metabolites issued form O-demethylations), with the
main one accounting for 5% of parent exposure.
Excreted as metabolites into the urine (4%) and faeces (76%).
Check Digit Verification of cas no
The CAS Registry Mumber 183133-96-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,8,3,1,3 and 3 respectively; the second part has 2 digits, 9 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 183133-96:
(8*1)+(7*8)+(6*3)+(5*1)+(4*3)+(3*3)+(2*9)+(1*6)=132
132 % 10 = 2
So 183133-96-2 is a valid CAS Registry Number.
183133-96-2Relevant articles and documents
Synthesis and biological evaluation of novel cabazitaxel analogues
Ren, Sumei,Zhang, Minmin,Wang, Yujie,Guo, Jia,Wang, Junfei,Li, Yingxia,Ding, Ning
, (2021/06/07)
Cabazitaxel is one of the most recently FDA-approved taxane anticancer agent. In view of the advantages in preclinical and clinical data of cabazitaxel over former toxoids, the synthesis and biological evaluation of novel cabazitaxel analogues were conducted. First, a novel semi-synthesis of cabazitaxel was described. This strategy is concise and efficient, which needs five steps from the 10-deacetylbaccatin III (10-DAB) moiety and a commercially available C13 side chain precursor with a 32% overall yield. Besides, this strategy avoids using many hazardous reagents that involved in the previously reported processes. Then, a panel of cabazitaxel analogues were prepared basing on this strategy. The cytotoxicity evaluations showed that the majority of these cabazitaxel analogues are potent against both A549 and KB cells and their corresponding drug-resistant cell lines KB/VCR, and A549/T, respectively. Further in vivo antitumor efficacies assessment of 7,10-di-O-methylthiomethyl (MTM) modified cabazitaxel (compounds 16 and 19) on SCID mice A549 xenograft model showed they both had similar antitumor activity to the cabazitaxel. Since compound 19 was observed causing more body wight loss on the mice than 16, these preliminary studies suggest 16 might be a potent drug candidate for further preclinical evaluation.
Acid-sensitive PEGylated cabazitaxel prodrugs for antitumor therapy
Liu, Tao,Zou, Hui,Mu, Jingqing,Yu, Na,Xu, Yang,Liu, Guohua,Liang, Xingjie,Guo, Shutao
supporting information, p. 1751 - 1754 (2021/03/08)
Although the antitumor drug cabazitaxel shows great therapeutic potential, its high toxicity and poor water solubility limit its utility. However, the use of stimuli-responsive prodrugs is a promising strategy for overcoming these limitations. Herein, we report the synthesis of two highly water soluble, acid-sensitive PEGylated acyclic-ketal-linked cabazitaxel prodrugs (PKCs) with improved antitumor efficacy. In an acidic tumor microenvironment, the PKCs hydrolyzed rapidly to release the native drug, whereas they were stable in the normal physiological environment. Compared with cabazitaxel injection, the PKCs had much higher maximum tolerated doses; and in an MDA-MB-231 subcutaneous xenograft nude mouse model, the PKCs showed better antitumor efficacy and safety than cabazitaxel injection. The prodrug strategy reported herein could be useful for the development of other water soluble, acid-sensitive prodrugs with improved efficacy.
Taxane anti-tumor drug KABA docetaxel synthesis method
-
, (2017/08/25)
The invention relates to a novel synthesis method of taxane antitumor drug cabazitaxel. The method relates to six-step reaction. Firstly, a key intermediate compound 7 as shown in the specification is obtained, and then reacts with di-tert-butyl dicarbonate ester (Boc)2O, so as to obtain the final product cabazitaxel. The whole reaction process does not relate to low-temperature operation and column chromatography purification, and the method is easy to operate, convenient to purify, and easy in mass production.
