Epothilone
| 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 | |
Epothilonesare 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 asmetabolitesproduced by the soil-dwellingmyxobacteriumSorangium cellulosum.[3]As of September 2008[update],epothilonesAtoFhave 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 forpaclitaxelwhich 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]
History
[edit]The structure of epothilone A was determined in 1996 usingx-ray crystallography.[7]
Mechanism of action
[edit]The principal mechanism of the epothilone class is the inhibition of themicrotubulefunction.[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 vitroand 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]
Medical use and research
[edit]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 cancertrial when added tocapecitabine.[14]
One synthetic analog,ixabepilone,was approved in October 2007 by the United StatesFood and Drug Administrationfor use in the treatment of aggressive metastatic or locally advancedbreast cancerthat no longer responds to currently available chemotherapies.[15]In November 2008, theEMEArefused a marketing authorization for ixabepilone.[16]
Epothilone B, with the generic drug namepatupilone,was proven to contain potentin vivoanticancer 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 syntheticsagopilonewere tested in phase II trials andBMS-310705was tested in phase I trials). Patupilone failed a phase III trial forovarian cancerin 2010.[18]
Results of a phase III trial withixabepilone(BMS-247550) in combination withcapecitabinein metastatic breast cancer have been announced (2007 – leading to FDA approval).[19]
Total synthesis
[edit]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 metathesisprecursor via analdol reactionand then anesterificationcoupling.Grubbs' catalystwas employed to close the bis terminal olefin of the precursor compound. The resulting compounds were cis- and trans-macrocyclic isomers with distinctstereocenters.Epoxidationof 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,and3as the building blocks (Figure 1).
As seen in Figure 2, keto acid1was generated from the keto aldehyde that was converted to the silyl ether viaasymmetric allylborationandsilylationof the resulting alcohol.Ozonolysisof the silyl ether andLindgren–Pinnickoxidation of the aldehyde afforded the keto acid. Ketone2was constructed viaEnders alkylationstarting from the hydrazone. Ozonolysis, the last step of the Enders alkylation, was followed by reduction of the aldehyde and silylation of the resulting alcohol.Hydrogenolysisof the benzyl ether gave the alcohol, which was oxidized underSwern conditionand alkylated with theGrignard reagentto yield the secondary alcohol. Oxidation of this alcohol with theLey–Griffith reagentgave the desired ketone. Thiazole3was 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 tetroxideto a diol that was cleaved withlead tetraacetateto furnish the aldehyde. Reduction, iodination, and treatment with triphenylphosphine led to phosphonium salt.
Fragments1,2,and3were reacted with each other to deliver epothilone B in an approach includingWittig reaction,aldol reaction,andYamaguchi esterification(Figure 3). Preparativethin-layer chromatographywas used to separate the diastereomers.
Biosynthesis
[edit]Epothilone B is a 16-memberedpolyketidemacrolactonewith a methylthiazolegroup 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 acysteineincorporated by anonribosomal peptide synthetase(NRPS). In this biosynthesis, both PKS and NRPS usecarrier proteins,which have been post-translationally modified byphosphopantetheinegroups, to join the growing chain. PKS usescoenzyme-Athioester 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 alsomethylatethe α carbon of the substrate. NRPS, on the other hand, usesamino acidsactivated 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 anacetateunit 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 groupswas derived from the propionate extender unit, while the second methyl group was integrated by a C-methyl-transferase domain.[27]
See also
[edit]References
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- ^Forli, Stefano (2014)."Epothilones: from discovery to clinical trials".Current Topics in Medicinal Chemistry.14(20): 2312–2321.doi:10.2174/1568026614666141130095855.PMC4629788.PMID25434353.
- ^"Epothilone - an overview | ScienceDirect Topics".sciencedirect.Retrieved2022-06-18.
- ^H. Spreitzer (September 15, 2008). "Neue Wirkstoffe – Sagobepilon – eine synthetische Variation von Epothilon B als Hoffnungsträger gegen Krebs".Österreichische Apothekerzeitung(in German) (19/2008): 978.
- ^Julien, B.; Shah, S. (2002)."Heterologous Expression of Epothilone Biosynthetic Genes in Myxococcus xanthus".Antimicrob. Agents Chemother.46(9): 2772–8.doi:10.1128/AAC.46.9.2772-2778.2002.PMC127399.PMID12183227.
- ^Muhlradt, P.F.; Sasse, F. (1997). "Epothilone B stabilizes microtubuli of macrophages like taxol without showing taxol-like endotoxin activity".Cancer Research.57(16): 3344–6.PMID9269992.
- ^Höfle, G.; Bedorf, N.; Steinmertz, H.; Schomburg, D.; Gerth, K.; Reichenbach, H. (1996). "Epothilone A and B—Novel 16-Membered Macrolides with Cytotoxic Activity: Isolation, Crystal Structure, and Conformation in Solution".Angew. Chem.35(1314): 1567.doi:10.1002/anie.199615671.
- ^Goodin S, Kane MP, Rubin EH (May 2004)."Epothilones: mechanism of action and biologic activity".J. Clin. Oncol.22(10): 2015–25.doi:10.1200/JCO.2004.12.001.PMID15143095.Archived fromthe originalon 2006-02-13.Retrieved2006-05-14.
- ^abBalog, D. M.; Meng, D.; Kamanecka, T.; Bertinato, P.; Su, D.-S.; Sorensen, E. J.; Danishefsky, S. J. (1996). "Totalsynthese von (—)-Epothilon A".Angew. Chem.108(23–24): 2976.Bibcode:1996AngCh.108.2976B.doi:10.1002/ange.19961082318.
- ^Jordan MA, Wilson L (April 2004). "Microtubules as a target for anticancer drugs".Nature Reviews Cancer.4(4): 253–65.doi:10.1038/nrc1317.PMID15057285.S2CID10228718.
- ^Ganguly A, Yang H, Cabral F (November 2010)."Paclitaxel-dependent cell lines reveal a novel drug activity".Mol. Cancer Ther.9(11): 2914–23.doi:10.1158/1535-7163.MCT-10-0552.PMC2978777.PMID20978163.
- ^"New Drug Approvals in China in 2021".diaglobal.org.2 May 2022.
- ^Villegas, Cecilia; González-Chavarría, Iván; Burgos, Viviana; Iturra-Beiza, Héctor; Ulrich, Henning; Paz, Cristian (January 2023)."Epothilones as Natural Compounds for Novel Anticancer Drugs Development".International Journal of Molecular Sciences.24(7): 6063.doi:10.3390/ijms24076063.ISSN1422-0067.PMC10093981.PMID37047035.
- ^Utidelone Active in Pretreated, Metastatic Breast Cancer. June 2016
- ^"Medical News Today: FDA Approves IXEMPRA(TM) (ixabepilone), A Semi-Synthetic Analog Of Epothilone B, For The Treatment Of Advanced Breast Cancer".Archived fromthe originalon 2011-05-16.Retrieved2009-02-17.
- ^London, 20 November 2008 Doc. Ref. EMEA/602569/2008
- ^Ojima, I.; Vite, G.D.; Altmann, K.H.;2001Anticancer Agents: Frontiers in Cancer Chemotherapy.American Chemical Society, Washington, DC.
- ^"ESMO: Failed Trials Dominate Gyn Cancer Session".14 October 2010. Archived fromthe originalon 18 June 2010.Retrieved26 October2010.
- ^"Phase III Ixabepilone Study Demonstrated Significant Improvement In Progression-Free Survival In Patients With Advanced Metastatic Breast Cancer".Medical News Today. 4 June 2007.
- ^Luduvico, I.; Hyaric, M. L.; Almeida, M. V.; Da Silva, A. D. (2006). "Synthetic Methodologies for the Preparation of Epothilones and Analogs".Mini-Reviews in Organic Chemistry(Review).3:49–75.doi:10.2174/157019306775474194.
- ^Su, D.-S.; Meng, D.; Bertinato, P.; Balog, D. M.; Sorensen, E. J.; Danishefsky, S. J.; Zheng, Y.-H.; Chou, T.-C.; He, L.; Horwitz, S. B. (1997). "Total Synthesis of(–)-Epothilone B: An Extension of the Suzuki Coupling Method and Insights into Structure–Activity Relationships of the Epothilones".Angew. Chem. Int. Ed. Engl.36(7): 757.doi:10.1002/anie.199707571.
- ^Yang, Z.; He, Y.; Vourloumis, D.;Vallberg, H.;Nicolaou, K. C. (1997). "Total Synthesis of Epothilone A: The Olefin Metathesis Approach".Angew. Chem. Int. Ed. Engl.36(12): 166.doi:10.1002/anie.199701661.
- ^Schinzer, D.; Limberg, A.; Bauer, A.; Böhm, O. M.; Cordes, M. (1997). "Total Synthesis of(−)-Epothilone A".Angew. Chem. Int. Ed. Engl.36(5): 523.doi:10.1002/anie.199705231.
- ^Mulzer, J.; Mantoulidis, A.; Öhler, E. (2000). "Total syntheses of epothilones B and D".J. Org. Chem.65(22): 7456–67.doi:10.1021/jo0007480.PMID11076603.
- ^Bode, J. W.; Carreira, E. M. (2001). "Stereoselective syntheses of epothilones A and B via directed nitrile oxide cycloaddition".J. Am. Chem. Soc.123(15): 3611–2.doi:10.1021/ja0155635.PMID11472140.
- ^Nicolaou, K.C.; Ninkovic, S.; Sarabia, F.; Vourloumis, D.; He, Y.; Vallberg, H.; Finlay, M.R.V.; Yang, Z. (1997). "Total Syntheses of Epothilones A and B via a Macrolactonization-Based Strategy".J. Am. Chem. Soc.119(34): 7974.doi:10.1021/ja971110h.
- ^abcMolnar, I.; Schupp, T.; Ono, M.; Zirkle, RE.; Milnamow, M.; Nowak-Thompson, B.; Engel, N.; Toupet, C.; Stratmann, A.; Cyr, DD.; Gorlach, J.; Mayo, JM.; Hu, A.; Goff, S.; Schmid, J.; Ligon, JM. (2000)."The biosynthetic gene cluster for the microtubule-stabilizing agents epothilones A and B from Sorangium cellulosum So ce90".Chemistry and Biology.7(2): 97–109.doi:10.1016/S1074-5521(00)00075-2.PMID10662695.