189453-10-9 Usage
Description
Epothilone D is a desoxy form of epothilone B, a microtubule-stabilizing agent with potential anti-neoplastic actions. It is a natural macrolide that exhibits high potency in both taxane-sensitive and taxane-resistant cancer models. Epothilone D is known for its ability to stabilize malignant cells' microtubules, arrest mitosis, and inhibit the growth of a variety of cancer cells. It is also brain penetrant, reducing neurodegeneration in aged tau transgenic mice and attenuating nigrostriatal degeneration in a mouse model of Parkinson's disease. Chemically, it is an epithilone C in which the hydrogen at position 13 of the oxacyclohexadec-13-ene-2,6-dione macrocycle has been replaced by a methyl group, and it appears as a white foam.
Uses
Used in Anticancer Applications:
Epothilone D is used as a cytotoxic macrolide for inhibiting cancer cells by a mechanism similar to paclitaxel, making it effective against paclitaxel-resistant tumors as well. It is currently in phase I clinical testing for patients with advanced solid tumors. Epothilones, including Epothilone D, bind to the same hepatic sites as paclitaxel (Taxol) in a 1:1 stoichiometric ratio of α, β-tubulin heterodimers.
Used in Neurodegenerative Disease Applications:
Epothilone D is used as a neuroprotective agent for reducing neurodegeneration in aged tau transgenic mice. It improves axonal transport, decreases tau neuropathology, and reduces hippocampal neuron loss. Additionally, it rescues microtubule defects and attenuates nigrostriatal degeneration in a mouse model of Parkinson's disease.
in vitro
epothilone d is a more potent microtubule stabilizer in vitro than epothilone a or b. in vitro, epothilone d showed potent cytotoxicity in a panel of human tumor cell lines, with similar potency to paclitaxel. it also showed definite advantage over paclitaxel in drug-resistant cell lines, and retained its cytotoxicity against a multidrug resistant cell line over-expressing p-glycoprotein [1].
in vivo
in vivo, antitumor efficacy of epothilone d has been observed in both paclitaxel sensitive and resistant xenografts, as well as certain multidrug resistant xenografts including a doxorubinresistant ccrf-cem leukemic cell xenograft [1].
IC 50
2.9 nm for mcf-7 cell line; 2.7 nm for kb-31 cell line; 9.5 nm for ccrf-cem cell line
references
[1] konner j, grisham rn, park j, o'connor oa, cropp g, johnson r, hannah al, hensley ml, sabbatini p, mironov s, danishefsky s, hyman d, spriggs dr, dupont j, aghajanian c. phase i clinical, pharmacokinetic, and pharmacodynamic study of kos-862 (epothilone d) in patients with advanced solid tumors and lymphoma. invest new drugs. 2012 dec;30(6):2294-302. doi: 10.1007/s10637-011-9765-7.
Check Digit Verification of cas no
The CAS Registry Mumber 189453-10-9 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,8,9,4,5 and 3 respectively; the second part has 2 digits, 1 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 189453-10:
(8*1)+(7*8)+(6*9)+(5*4)+(4*5)+(3*3)+(2*1)+(1*0)=169
169 % 10 = 9
So 189453-10-9 is a valid CAS Registry Number.
InChI:InChI=1/C27H41NO5S/c1-16-9-8-10-17(2)25(31)19(4)26(32)27(6,7)23(29)14-24(30)33-22(12-11-16)18(3)13-21-15-34-20(5)28-21/h11,13,15,17,19,22-23,25,29,31H,8-10,12,14H2,1-7H3/b16-11-,18-13+/t17-,19+,22?,23-,25-/m0/s1
189453-10-9Relevant articles and documents
Epothilone D and its 9-Methyl analogues: Combinatorial syntheses, conformation, and biological activities
Sang, Feng,Feng, Peng,Chen, Jie,Ding, Yahui,Duan, Xiyan,Zhai, Jiadai,Ma, Xiaoyan,Zhang, Bin,Zhang, Quan,Lin, Jianping,Chen, Yue
, p. 321 - 332 (2013)
Epothilone D (Epo D) and its 9-Methyl conformational analogues were synthesized through a highly efficient combinatorial approach. The fragment E was synthesized in 11 total steps with 6 longest linear steps, and each aldehyde B was prepared via a 3-step sequence. Starting from the common precursor E and a suitable aldehydes B, each target molecule were obtained in only 4 steps. The 9-(S)-epo D and 9-(R)-epo D demonstrated significant difference in inhibition activities against cancer cell lines and in conformational analysis.
The Total Synthesis of Epothilone D as a Yardstick for Probing New Methodologies
Haydl, Alexander M.,Breit, Bernhard
supporting information, p. 541 - 545 (2017/01/18)
Here, a concise and highly convergent synthesis of epothilone D was investigated, relying on fragments of equal complexity that could be prepared in gram scale quantities. The strategy to construct the fragments includes the use of a previously reported enantiospecific zinc-catalyzed cross-coupling of an α-hydroxy ester triflate with a Grignard reagent, the application of a hydroboration/boron–magnesium exchange sequence for the rapid construction of the Z-substituted trisubstituted double bond present in the natural product, and a Noyori-type hydrogenation to install the β-hydroxy ester moiety of the southern part. The key to success is the diastereoselective head-to-tail macrolactonization by an intramolecular addition of the corresponding ω-alkynyl-substituted carboxylic acids to construct a new stereocenter in the macrocyclic core structure in one single step.
Total synthesis of epothilone D: The nerol/macroaldolization approach
Wessjohann, Ludger A.,Scheid, Guenther O.,Eichelberger, Uwe,Umbreen, Sumaira
, p. 10588 - 10595 (2013/11/19)
A highly convergent and stereocontrolled synthesis of epothilone D (4) is reported. Key features are a cheap and Z-selective synthesis of the northern half based on nerol and acetoacetate and chromium(II)-mediated Reformatsky reactions as a powerful tool for chemoselective asymmetric carbon-carbon bond formations, including an unusual stereospecific macroaldolization.