Epothilone

{{short description|Class of chemical compounds}} {| class="toccolours" border="1" style="float: right; clear: right; margin: 0 0 1em 1em; border-collapse: collapse;" ! {{Chemical datatable header}}| Epothilones |- | align="center" colspan="2" bgcolor="#ffffff"| 250px|Epothilones A (R = H) and B (R = Me) Epothilones A (R = H) and B (R = CH3) |- | Chemical formulae | '''A:''' C26H39NO6S '''B:''' C27H41NO6S |- | Molecular masses | '''A:''' 493.66 g/mol '''B:''' 507.68 g/mol |- | CAS numbers | '''A:''' 152044-53-6 '''B:''' 152044-54-7 |- | PubChem | '''A:''' 448799 '''B:''' 448013 |- | align="center" colspan="2" bgcolor="#ffffff"| 250px|Epothilones C (R = H) and D (R = Me) Epothilones C (R = H) and D (R = CH3) |- | Chemical formulae | '''C:''' C26H39NO5S '''D:''' C27H41NO5S |- | Molecular masses | '''C:''' 477.66 g/mol '''D:''' 491.68 g/mol |- | CAS numbers | '''C:''' 186692-73-9 '''D:''' 189453-10-9 |- | PubChem | '''C:''' 9891226 '''D:''' 447865 |- | align="center" colspan="2" bgcolor="#ffffff"| 250px|Epothilones E (R = H) and F (R = Me) Epothilones E (R = H) and F (R = CH3) |- | Chemical formulae | '''E:''' C26H39NO7S '''F:''' C27H41NO7S |- | Molecular masses | '''E:''' 509.66 g/mol '''F:''' 523.68 g/mol |- | CAS numbers | '''E:''' 201049-37-8 '''F:''' 208518-52-9 |- | PubChem | '''E:''' 9806341 '''F:''' 9914741 |- | {{Chemical datatable header}} | Disclaimer and references |}

'''Epothilones''' are a class of potential cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin, but in early trials, epothilones have better efficacy and milder adverse effects than taxanes.<ref>{{cite book |author1=Rosenberg, Steven |author2=DeVita, Vincent T. |author3=Hellman, Samuel |title=Cancer: Principles & Practice of Oncology |url=https://archive.org/details/cancerprinciples01devi |url-access=registration |publisher=Lippincott Williams & Wilkins |location=Hagerstwon, MD |year=2005 |isbn=978-0-7817-4450-8 |oclc=232304182 |edition=7th }}{{pn|date=October 2025}}</ref><ref>{{Cite journal |last=Forli |first=Stefano |date=2014 |title=Epothilones: from discovery to clinical trials |journal=Current Topics in Medicinal Chemistry |language=en |volume=14 |issue=20 |pages=2312–2321 |doi=10.2174/1568026614666141130095855 |pmid=25434353|pmc=4629788 }}</ref>

Epothilones were originally identified as metabolites produced by the soil-dwelling myxobacterium ''Sorangium cellulosum''.<ref>{{cite book |last1=Avendaño |first1=Carmen |last2=Menéndez |first2=J. Carlos |title=Medicinal Chemistry of Anticancer Drugs |chapter=Anticancer drugs targeting tubulin and microtubules |date=2023 |pages=445–491 |doi=10.1016/B978-0-12-818549-0.00017-0 |isbn=978-0-12-818549-0 |quote=The epothilones A and B are naturally occurring 16-membered macrolides that were isolated in 1993 from the myxobacterium Sorangium cellulosum and first employed as agrochemical antifungal agents. }}</ref> {{As of|September 2008}}, epothilones '''A''' to '''F''' have been identified and characterized.<ref>{{cite journal | author = H. Spreitzer | date = September 15, 2008 | title = Neue Wirkstoffe – Sagobepilon – eine synthetische Variation von Epothilon B als Hoffnungsträger gegen Krebs | journal = Österreichische Apothekerzeitung | issue = 19/2008 | pages = 978 | language = de }}</ref>

Early studies in cancer cell lines and human cancer patients indicate superior efficacy to the taxanes. Their mechanism of action is similar, but their chemical structure is simpler. Due to their better water solubility, cremophors (solubilizing agents used for paclitaxel which can affect cardiac function and cause severe hypersensitivity) are not needed.<ref>{{cite journal |last1=Julien |first1=Bryan |last2=Shah |first2=Sanjay |title=Heterologous Expression of Epothilone Biosynthetic Genes in Myxococcus xanthus |journal=Antimicrobial Agents and Chemotherapy |date=September 2002 |volume=46 |issue=9 |pages=2772–2778 |doi=10.1128/AAC.46.9.2772-2778.2002 |pmid=12183227 |pmc=127399 }}</ref> Endotoxin-like properties known from paclitaxel, like activation of macrophages synthesizing inflammatory cytokines and nitric oxide, are not observed for epothilone B.<ref>{{cite journal |last1=Mühlradt |first1=Peter F. |last2=Sasse |first2=Florenz |title=Epothilone B Stabilizes Microtubuli of Macrophages Like Taxol without Showing Taxol-like Endotoxin Activity |journal=Cancer Research |date=15 August 1997 |volume=57 |issue=16 |pages=3344–3346 |pmid=9269992 |url=https://aacrjournals.org/cancerres/article/57/16/3344/503472/Epothilone-B-Stabilizes-Microtubuli-of-Macrophages }}</ref>

==History== The structure of epothilone A was determined in 1996 using x-ray crystallography.<ref>{{cite journal |last1=Höfle |first1=Gerhard |last2=Bedorf |first2=Norbert |last3=Steinmetz |first3=Heinrich |last4=Schomburg |first4=Dietmar |last5=Gerth |first5=Klaus |last6=Reichenbach |first6=Hans |title=Epothilone A and B—Novel 16-Membered Macrolides with Cytotoxic Activity: Isolation, Crystal Structure, and Conformation in Solution |journal=Angewandte Chemie International Edition in English |date=July 1996 |volume=35 |issue=13–14 |pages=1567–1569 |doi=10.1002/anie.199615671 }}</ref>

==Mechanism of action== The principal mechanism of the epothilone class is the inhibition of the microtubule function.<ref>{{cite journal |last1=Goodin |first1=Susan |last2=Kane |first2=Michael P. |last3=Rubin |first3=Eric H. |title=Epothilones: Mechanism of Action and Biologic Activity |journal=Journal of Clinical Oncology |date=15 May 2004 |volume=22 |issue=10 |pages=2015–2025 |doi=10.1200/JCO.2004.12.001 |pmid=15143095 }}</ref> Microtubules are essential to cell division, and epothilones, therefore, stop cells from properly dividing. Epothilone B possesses the same biological effects as paclitaxel both ''in 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.<ref name="Balog1996">{{cite journal |last1=Balog |first1=Aaron |last2=Meng |first2=Dongfang |last3=Kamenecka |first3=Ted |last4=Bertinato |first4=Peter |last5=Su |first5=Dai-Shi |last6=Sorensen |first6=Erik J. |last7=Danishefsky |first7=Samuel J. |title=Totalsynthese von (—)-Epothilon A |journal=Angewandte Chemie |date=16 December 1996 |volume=108 |issue=23–24 |pages=2976–2978 |doi=10.1002/ange.19961082318 |bibcode=1996AngCh.108.2976B }}</ref> The ability of epothilone to inhibit spindle function is generally attributed to its suppression of microtubule dynamics;<ref>{{cite journal |last1=Jordan |first1=Mary Ann |last2=Wilson |first2=Leslie |title=Microtubules as a target for anticancer drugs |journal=Nature Reviews Cancer |date=April 2004 |volume=4 |issue=4 |pages=253–265 |doi=10.1038/nrc1317 |pmid=15057285 }}</ref> 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.<ref>{{cite journal |last1=Ganguly |first1=Anutosh |last2=Yang |first2=Hailing |last3=Cabral |first3=Fernando |title=Paclitaxel-Dependent Cell Lines Reveal a Novel Drug Activity |journal=Molecular Cancer Therapeutics |date=November 2010 |volume=9 |issue=11 |pages=2914–2923 |doi=10.1158/1535-7163.MCT-10-0552 |pmid=20978163 |pmc=2978777 }}</ref>

==Medical use and research==

Epothilone D, with the generic drug name utidelone, was approved in China in 2021 for the treatment of metastatic breast cancer.<ref>{{cite web | url = https://globalforum.diaglobal.org/issue/may-2022/new-drug-approvals-in-china-in-2021/ | title = New Drug Approvals in China in 2021 | website = diaglobal.org| date = 2 May 2022 }}</ref><ref name=Villegas>{{Cite journal |last1=Villegas |first1=Cecilia |last2=González-Chavarría |first2=Iván |last3=Burgos |first3=Viviana |last4=Iturra-Beiza |first4=Héctor |last5=Ulrich |first5=Henning |last6=Paz |first6=Cristian |date=January 2023 |title=Epothilones as Natural Compounds for Novel Anticancer Drugs Development |journal=International Journal of Molecular Sciences |volume=24 |issue=7 |pages=6063 |doi=10.3390/ijms24076063 |pmid=37047035 |pmc=10093981 |doi-access=free }}</ref> Utidelone has shown benefits in a phase III breast cancer trial when added to capecitabine.<ref>{{cite news |last1=Lawrence |first1=Leah |title=Utidelone Active in Pretreated, Metastatic Breast Cancer {{!}} CancerNetwork |url=https://www.cancernetwork.com/view/utidelone-active-pretreated-metastatic-breast-cancer |work=CancerNetwork |date=8 October 2025 }}</ref>

One synthetic analog, ixabepilone, was approved in October 2007 by the United States Food and Drug Administration for use in the treatment of aggressive metastatic or locally advanced breast cancer that no longer responds to currently available chemotherapies.<ref>{{Cite web |url=http://www.medicalnewstoday.com/articles/85726.php |title=Medical News Today: FDA Approves IXEMPRA(TM) (ixabepilone), A Semi-Synthetic Analog Of Epothilone B, For The Treatment Of Advanced Breast Cancer |access-date=2009-02-17 |archive-date=2011-05-16 |archive-url=https://web.archive.org/web/20110516020456/http://www.medicalnewstoday.com/articles/85726.php |url-status=dead }}</ref> In November 2008, the EMEA refused a marketing authorization for ixabepilone.<ref>London, 20 November 2008 Doc. Ref. EMEA/602569/2008</ref>

Epothilone B, with the generic drug name patupilone, was proven to contain potent ''in vivo'' anticancer activities at tolerated dose levels in several human xenograft models.<ref>{{cite book |title=Anticancer Agents |series=ACS Symposium Series |date=2001 |volume=796 |doi=10.1021/bk-2001-0796 |isbn=978-0-8412-3745-2 }}{{pn|date=October 2025}}</ref> As a result, patupilone and various analogs underwent various clinical phases.

Patupilone and the fully synthetic sagopilone were tested in phase II trials and BMS-310705 was tested in phase I trials). Patupilone failed a phase III trial for ovarian cancer in 2010.<ref>{{cite news |url=http://www.medicalnewstoday.com/articles/190450.php |title=ESMO: Failed Trials Dominate Gyn Cancer Session |date=14 October 2010 |access-date=26 October 2010 |archive-date=18 June 2010 |archive-url=https://web.archive.org/web/20100618124238/http://www.medicalnewstoday.com/articles/190450.php |url-status=dead }}</ref>

Results of a phase III trial with ixabepilone (BMS-247550) in combination with capecitabine in metastatic breast cancer have been announced (2007 – leading to FDA approval).<ref>{{cite news|url=http://www.medicalnewstoday.com/medicalnews.php?newsid=72986 |title=Phase III Ixabepilone Study Demonstrated Significant Improvement In Progression-Free Survival In Patients With Advanced Metastatic Breast Cancer |date=4 June 2007 |publisher=Medical News Today }}</ref>

==Total synthesis== Due to the high potency and clinical need for cancer treatments, epothilones have been the target of many total syntheses.<ref>{{cite journal |last1=Luduvico |first1=Inacio |last2=Hyaric |first2=Mireille L. |last3=Almeida |first3=Mauro V. De |last4=Silva |first4=Adilson D. Da |title=Synthetic Methodologies for the Preparation of Epothilones and Analogs |journal=Mini-Reviews in Organic Chemistry |date=2006 |volume=3 |issue=1 |pages=49–75 |doi=10.2174/157019306775474194 }}{{predatory}}</ref> The first group to publish the total synthesis of epothilones was S. J. Danishefsky ''et al.'' in 1996.<ref name="Balog1996"/><ref>{{cite journal |last1=Su |first1=Dai-Shi |last2=Meng |first2=Dongfang |last3=Bertinato |first3=Peter |last4=Balog |first4=Aaron |last5=Sorensen |first5=Erik J. |last6=Danishefsky |first6=Samuel J. |last7=Zheng |first7=Yu-Huang |last8=Chou |first8=Ting-Chao |last9=He |first9=Lifeng |last10=Horwitz |first10=Susan B. |title=Total Synthesis of (–)-Epothilone B: An Extension of the Suzuki Coupling Method and Insights into Structure–Activity Relationships of the Epothilones |journal=Angewandte Chemie International Edition in English |date=18 April 1997 |volume=36 |issue=7 |pages=757–759 |doi=10.1002/anie.199707571 }}</ref> This total synthesis of epothilone A was achieved via an intramolecular ester enolate-aldehyde condensation. Other syntheses of epothilones have been published by Nicolaou,<ref>{{cite journal |last1=Yang |first1=Zhen |last2=He |first2=Yun |last3=Vourloumis |first3=Dionisios |last4=Vallberg |first4=Hans |last5=Nicolaou |first5=K. C. |title=Total Synthesis of Epothilone A: The Olefin Metathesis Approach |journal=Angewandte Chemie International Edition in English |date=3 February 1997 |volume=36 |issue=1–2 |pages=166–168 |doi=10.1002/anie.199701661 }}</ref> Schinzer,<ref>{{cite journal |last1=Schinzer |first1=Dieter |last2=Limberg |first2=Anja |last3=Bauer |first3=Armin |last4=Böhm |first4=Oliver M. |last5=Cordes |first5=Martin |title=Total Synthesis of (−)-Epothilone A |journal=Angewandte Chemie International Edition in English |date=14 March 1997 |volume=36 |issue=5 |pages=523–524 |doi=10.1002/anie.199705231 }}</ref> Mulzer,<ref>{{cite journal |last1=Mulzer |first1=Johann |last2=Mantoulidis |first2=Andreas |last3=Öhler |first3=Elisabeth |title=Total Syntheses of Epothilones B and D |journal=The Journal of Organic Chemistry |date=November 2000 |volume=65 |issue=22 |pages=7456–7467 |doi=10.1021/jo0007480 |pmid=11076603 }}</ref> and Carreira.<ref>{{cite journal |last1=Bode |first1=Jeffrey W. |last2=Carreira |first2=Erick M. |title=Stereoselective Syntheses of Epothilones A and B via Directed Nitrile Oxide Cycloaddition 1 |journal=Journal of the American Chemical Society |date=April 2001 |volume=123 |issue=15 |pages=3611–3612 |doi=10.1021/ja0155635 |pmid=11472140 |bibcode=2001JAChS.123.3611B }}</ref> In this approach, key building blocks aldehyde, glycidols, and ketoacid were constructed and coupled to the olefin metathesis precursor via an aldol reaction and then an esterification 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 distinct stereocenters. 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 of K. C. Nicolaou.<ref name="Nicolaou1997">{{cite journal |last1=Nicolaou |first1=K. C. |last2=Ninkovic |first2=S. |last3=Sarabia |first3=F. |last4=Vourloumis |first4=D. |last5=He |first5=Y. |last6=Vallberg |first6=H. |last7=Finlay |first7=M. R. V. |last8=Yang |first8=Z. |title=Total Syntheses of Epothilones A and B via a Macrolactonization-Based Strategy |journal=Journal of the American Chemical Society |date=August 1997 |volume=119 |issue=34 |pages=7974–7991 |doi=10.1021/ja971110h |bibcode=1997JAChS.119.7974N }}</ref> The retrosynthetic analysis revealed '''1''', '''2''', and '''3''' as the building blocks (Figure 1).

thumb|300px|Figure 1

As seen in Figure 2, keto acid '''1''' was generated from the keto aldehyde that was converted to the silyl ether via asymmetric allylboration and silylation of the resulting alcohol. Ozonolysis of the silyl ether and Lindgren–Pinnick oxidation of the aldehyde afforded the keto acid. Ketone '''2''' was constructed via Enders 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 under Swern condition and alkylated with the Grignard reagent to yield the secondary alcohol. Oxidation of this alcohol with the Ley–Griffith reagent gave the desired ketone. Thiazole '''3''' was synthesized from the ester, which was reduced with diisobutylaluminium hydride, and the aldehyde was reacted with the stabilized ylide in the Wittig reaction. Asymmetric allylboration of the α,β-unsaturated aldehyde and protection of the hydroxy group gave the silyl ether, whose terminal olefin was reacted with osmium tetroxide to a diol that was cleaved with lead tetraacetate to furnish the aldehyde. Reduction, iodination, and treatment with triphenylphosphine led to phosphonium salt.

thumb|300px|Figure 2

Fragments '''1''', '''2''', and '''3''' were reacted with each other to deliver epothilone B in an approach including Wittig reaction, aldol reaction, and Yamaguchi esterification (Figure 3). Preparative thin-layer chromatography was used to separate the diastereomers.

thumb|300px|Figure 3

==Biosynthesis== Epothilone B is a 16-membered polyketide macrolactone with a methylthiazole group connected to the macrocycle by an olefinic bond. The polyketide backbone was synthesized by type I polyketide synthase (PKS) and the thiazole ring was derived from a cysteine incorporated by a nonribosomal peptide synthetase (NRPS). In this biosynthesis, both PKS and NRPS use carrier proteins, which have been post-translationally modified by phosphopantetheine groups, to join the growing chain. PKS uses coenzyme-A thioester to catalyze the reaction and modify the substrates by selectively reducing the β carbonyl to the hydroxyl (Ketoreductase, KR), the alkene (Dehydratase, DH), and the alkane (Enoyl Reductase, ER). PKS-I can also methylate the α carbon of the substrate. NRPS, on the other hand, uses amino acids activated on the enzyme as aminoacyl adenylates. Unlike PKS, epimerization, N-methylation, and heterocycle formation occurs in the NRPS enzyme.<ref name="Molnar2000">{{cite journal |last1=Molnár |first1=I. |last2=Schupp |first2=T. |last3=Ono |first3=M. |last4=Zirkle |first4=R. |last5=Milnamow |first5=M. |last6=Nowak-Thompson |first6=B. |last7=Engel |first7=N. |last8=Toupet |first8=C. |last9=Stratmann |first9=A. |last10=Cyr |first10=D. D. |last11=Gorlach |first11=J. |last12=Mayo |first12=J. M. |last13=Hu |first13=A. |last14=Goff |first14=S. |last15=Schmid |first15=J. |last16=Ligon |first16=J. M. |title=The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90 |journal=Chemistry & Biology |date=February 2000 |volume=7 |issue=2 |pages=97–109 |doi=10.1016/s1074-5521(00)00075-2 |pmid=10662695 |doi-access=free }}</ref>

thumb|300px|Figure 4

thumb|400px|Figure 5

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 heterocyclization, 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 in '''Figure 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 an acetate unit onto the EPOS P complex, thus initiating the formation of the thiazoline ring by intramolecular cyclodehydration.<ref name="Molnar2000"/>

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 in '''Figure 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 the methyl groups was derived from the propionate extender unit, while the second methyl group was integrated by a C-methyl-transferase domain.<ref name="Molnar2000"/>

==See also== * Discodermolide

==References== {{Reflist}}

Category:Mitotic inhibitors Category:Epoxides Category:Thiazoles Category:Total synthesis Category:Lactams Category:Polyketides B