| Epothilones | |
|---|---|
 Epothilones A (R = H) and B (R = CH3) | |
| Chemical formulae | A: C26H39NO6S |
| Molecular masses | A: 493.66 g/mol |
| CAS numbers | A: 152044-53-6 |
| PubChem | A: 448799 |
 Epothilones C (R = H) and D (R = CH3) | |
| Chemical formulae | C: C26H39NO5S |
| Molecular masses | C: 477.66 g/mol |
| CAS numbers | C: 186692-73-9 |
| PubChem | C: 9891226 |
 Epothilones E (R = H) and F (R = CH3) | |
| Chemical formulae | E: C26H39NO7S |
| Molecular masses | E: 509.66 g/mol |
| CAS numbers | E: 201049-37-8 |
| PubChem | E: 9806341 |
| Disclaimer and references | |
Epothilones are a class of potential cancer drugs. Liketaxanes, they prevent cancer cells from dividing by interfering withtubulin, but in early trials, epothilones have better efficacy and milder adverse effects than taxanes.[1][2]
Epothilones were originally identified asmetabolites produced by the soil-dwellingmyxobacteriumSorangium cellulosum.[3] As of September 2008[update], epothilonesA toF have been identified and characterized.[4]
Early studies in cancer cell lines and human cancer patients indicate superior efficacy to thetaxanes. Their mechanism of action is similar, but their chemical structure is simpler. Due to their better water solubility, cremophors (solubilizing agents used forpaclitaxel which can affect cardiac function and cause severe hypersensitivity) are not needed.[5] Endotoxin-like properties known from paclitaxel, like activation of macrophages synthesizing inflammatory cytokines and nitric oxide, are not observed for epothilone B.[6]
The structure of epothilone A was determined in 1996 usingx-ray crystallography.[7]
The principal mechanism of the epothilone class is the inhibition of themicrotubule function.[8] Microtubules are essential to cell division, and epothilones, therefore, stop cells from properly dividing. Epothilone B possesses the same biological effects as paclitaxel bothin vitro and in cultured cells. This is because they share the same binding site, as well as binding affinity to the microtubule. Like paclitaxel, epothilone B binds to the αβ-tubulin heterodimer subunit. Once bound, the rate of αβ-tubulin dissociation decreases, thus stabilizing the microtubules. Furthermore, epothilone B has also been shown to induce tubulin polymerization into microtubules without the presence of GTP. This is caused by the formation of microtubule bundles throughout the cytoplasm. Finally, epothilone B also causes cell cycle arrest at the G2-M transition phase, thus leading to cytotoxicity and eventually cell apoptosis.[9] The ability of epothilone to inhibit spindle function is generally attributed to its suppression of microtubule dynamics;[10] but recent studies have demonstrated that suppression of dynamics occurs at concentrations lower than those needed to block mitosis. At higher antimitotic concentrations, paclitaxel appears to act by suppressing microtubule detachment from centrosomes, a process that is normally activated during mitosis. It is quite possible that epothilone can also act through a similar mechanism.[11]
Epothilone D, with the generic drug nameutidelone, was approved in China in 2021 for the treatment ofmetastatic breast cancer.[12][13] Utidelone has shown benefits in a phase IIIbreast cancer trial when added tocapecitabine.[14]
One synthetic analog,ixabepilone, was approved in October 2007 by the United StatesFood and Drug Administration for use in the treatment of aggressive metastatic or locally advancedbreast cancer that no longer responds to currently available chemotherapies.[15] In November 2008, theEMEA refused a marketing authorization for ixabepilone.[16]
Epothilone B, with the generic drug namepatupilone, was proven to contain potentin vivo anticancer activities at tolerated dose levels in several human xenograft models.[17] As a result, patupilone and various analogs underwent various clinical phases.
Patupilone and the fully syntheticsagopilone were tested in phase II trials andBMS-310705 was tested in phase I trials). Patupilone failed a phase III trial forovarian cancer in 2010.[18]
Results of a phase III trial withixabepilone (BMS-247550) in combination withcapecitabine in metastatic breast cancer have been announced (2007 – leading to FDA approval).[19]
Due to the high potency and clinical need for cancer treatments, epothilones have been the target of manytotal syntheses.[20] The first group to publish the total synthesis of epothilones was S. J. Danishefskyet al. in 1996.[9][21] This total synthesis of epothilone A was achieved via an intramolecular ester enolate-aldehyde condensation. Other syntheses of epothilones have been published byNicolaou,[22] Schinzer,[23]Mulzer,[24] andCarreira.[25] In this approach, key building blocksaldehyde,glycidols, and ketoacid were constructed and coupled to theolefin metathesis precursor via analdol reaction and then anesterification coupling.Grubbs' catalyst was employed to close the bis terminal olefin of the precursor compound. The resulting compounds were cis- and trans-macrocyclic isomers with distinctstereocenters.Epoxidation of cis- and trans-olefins yield epothilone A and its analogs.
One of the total syntheses of epothilone B is outlined below and was described by the laboratory ofK. C. Nicolaou.[26] The retrosynthetic analysis revealed1,2, and3 as the building blocks (Figure 1).
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As seen in Figure 2, keto acid1 was generated from the keto aldehyde that was converted to the silyl ether viaasymmetric allylboration andsilylation of the resulting alcohol.Ozonolysis of the silyl ether andLindgren–Pinnick oxidation of the aldehyde afforded the keto acid. Ketone2 was constructed viaEnders alkylation starting from the hydrazone. Ozonolysis, the last step of the Enders alkylation, was followed by reduction of the aldehyde and silylation of the resulting alcohol.Hydrogenolysis of the benzyl ether gave the alcohol, which was oxidized underSwern condition and alkylated with theGrignard reagent to yield the secondary alcohol. Oxidation of this alcohol with theLey–Griffith reagent gave the desired ketone. Thiazole3 was synthesized from the ester, which was reduced withdiisobutylaluminium hydride, and the aldehyde was reacted with the stabilized ylide in theWittig reaction. Asymmetric allylboration of the α,β-unsaturated aldehyde and protection of the hydroxy group gave the silyl ether, whose terminal olefin was reacted withosmium tetroxide to a diol that was cleaved withlead tetraacetate to furnish the aldehyde. Reduction, iodination, and treatment with triphenylphosphine led to phosphonium salt.
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Fragments1,2, and3 were reacted with each other to deliver epothilone B in an approach includingWittig reaction,aldol reaction, andYamaguchi esterification (Figure 3). Preparativethin-layer chromatography was used to separate the diastereomers.
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Epothilone B is a 16-memberedpolyketidemacrolactone with a methylthiazole group connected to the macrocycle by an olefinic bond. The polyketide backbone was synthesized by type Ipolyketide synthase (PKS) and the thiazole ring was derived from acysteine incorporated by anonribosomal peptide synthetase (NRPS). In this biosynthesis, both PKS and NRPS usecarrier proteins, which have been post-translationally modified byphosphopantetheine groups, to join the growing chain. PKS usescoenzyme-A thioester to catalyze the reaction and modify the substrates by selectively reducing the β carbonyl to thehydroxyl (Ketoreductase, KR), thealkene (Dehydratase, DH), and thealkane (Enoyl Reductase, ER). PKS-I can alsomethylate the α carbon of the substrate. NRPS, on the other hand, usesamino acids activated on the enzyme as aminoacyl adenylates. Unlike PKS,epimerization, N-methylation, and heterocycle formation occurs in the NRPS enzyme.[27]
Epothilone B starts with a 2-methyl-4-carboxythiazole starter unit, which was formed through the translational coupling between PKS, EPOS A (epoA) module, and NRPS, EPOS P(epoP) module. The EPOS A contains a modified β-ketoacyl-synthase (malonyl-ACP decarboxylase, KSQ), an acyltransferase (AT), an enoyl reductase (ER), and an acyl carrier protein domain (ACP). The EPOS P however, contains a heterocylization, an adenylation, an oxidase, and a thiolation domain. These domains are important because they are involved in the formation of the five-membered heterocyclic ring of thiazole. As seen inFigure 4, the EPOS P activates the cysteine and binds the activated cysteine as an aminoacyl-S-PCP. Once the cysteine has been bound, EPOS A loads anacetate unit onto the EPOS P complex, thus initiating the formation of the thiazoline ring by intramolecular cyclodehydration.[27]
Once the 2-methylthiazole ring has been made, it is then transferred to the PKS EPOS B (epoB), EPOS C (epoC), EPOS D (epoD), EPOS E (epoE), and EPOS F (epoF) for subsequent elongation and modification to generate the olefinic bond, the 16-membered ring, and the epoxide, as seen inFigure 5. One important thing to note is the synthesis of the gem-dimethyl unit in module 7. These two dimethyls were not synthesized by two successive C-methylations. Instead, one of themethyl groups was derived from the propionate extender unit, while the second methyl group was integrated by a C-methyl-transferase domain.[27]