ABSTRACT
It has been realized that FDA approved drugs may have more molecular targets than is commonly thought. Thus, to find the exact drug-target interactions (DTIs) is of great significance for exploring the new molecular mechanism of drugs. Here, we developed a multi-scale system pharmacology (MSSP) method for the large-scale prediction of DTIs. We used MSSP to integrate drug-related and target-related data from multiple levels, the network structural data formed by known drug-target relationships for predicting likely unknown DTIs. Prediction results revealed that Ixabepilone, an epothilone B analog for treating breast cancer patients, may target Bcl-2, an oncogene that contributes to tumor progression and therapy resistance by inhibiting apoptosis. Furthermore, we demonstrated that Ixabepilone could bind with Bcl-2 and decrease its protein expression in breast cancer cells. The down-regulation of Bcl-2 by Ixabepilone is resulted from promoting its degradation by affecting p-Bcl-2. We further found that Ixabepilone could induce autophagy by releasing Beclin1 from Beclin1/Bcl-2 complex. Inhibition of autophagy by knockdown of Beclin1 or pharmacological inhibitor augmented apoptosis, thus enhancing the antitumor efficacy of Ixabepilone against breast cancer cells in vitro and in vivo. In addition, Ixabepilone also decreases Bcl-2 protein expression and induces cytoprotective autophagy in human hepatic carcinoma and glioma cells. In conclusion, this study not only provides a feasible and alternative way exploring new molecular mechanisms of drugs by combing computation DTI prediction, but also reveals an effective strategy to reinforce the antitumor efficacy of Ixabepilone.
Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Epothilones/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Epothilones/chemical synthesis , Epothilones/chemistry , Female , Humans , Mammary Neoplasms, Experimental/drug therapy , Mammary Neoplasms, Experimental/metabolism , Mammary Neoplasms, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Epothilone is a kind of macrolide compound, which has anticancer activity and strong inhibitory effect on breast cancer and rectal cancer cells. Herein, the chemical and biological synthesis of epothilones and how to improve fermentation yield and separation methods were summarized and discussed.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/isolation & purification , Epothilones/biosynthesis , Epothilones/chemical synthesis , Epothilones/isolation & purification , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Ceramics/chemistry , Drug Screening Assays, Antitumor , Epothilones/pharmacology , Fermentation , Glycosylation , Humans , Mutation , Porosity , Secondary Metabolism , Streptomyces/genetics , Streptomyces/metabolism , Structure-Activity Relationship , Surface PropertiesABSTRACT
Epothilone, the macrolide compound produced by Sorangium cellulosum, has antitumor activity. Its anti-tumor mechanism is similar to that of paclitaxel, which promotes the polymerization of tubulin and induces apoptosis. Herein, 7-O-ß-d-galactosyl-polyethylene glycol-epothilone B 6 was synthesized. It showed that the toxicity of the synthesized compound was 1/182 of the epothilone B. In addition, compound 6 also had significant anticancer activity under the action of enzyme.
Subject(s)
Antineoplastic Agents, Phytogenic/chemical synthesis , Epothilones/chemistry , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Cell Proliferation/drug effects , Epothilones/chemical synthesis , Epothilones/pharmacology , Galactose/chemistry , Humans , MCF-7 Cells , Myxococcales/chemistry , Myxococcales/metabolism , Polyethylene Glycols/chemistry , SorangiumABSTRACT
Epothilones are a class of macrolide compounds. Their activities of tubulin polymerization and microtubule depolymerization inhibition like paclitaxel make them a new generation of antimitotic drugs. The mechanism of action is similar to that of paclitaxel, which can bind to tubulin and cause cancer cells to fail to undergo mitosis, thereby causing apoptosis in cancer cells. Epothilone is superior to paclitaxel in anti-tumor spectrum, anti-tumor activity, safety, water solubility and synthetic methods. It is expected to develop into a more effective anti-tumor drug than paclitaxel. Herein, the synthesis methods and activity of epothilone D were summarized and analyzed.
Subject(s)
Epothilones/chemical synthesis , Neoplasms/drug therapy , Tubulin Modulators/chemical synthesis , Cell Survival/drug effects , Clinical Trials as Topic , Drug Screening Assays, Antitumor , Epothilones/chemistry , Epothilones/pharmacology , Epothilones/therapeutic use , Humans , Mitosis/drug effects , Neoplasms/genetics , Paclitaxel/chemistry , Paclitaxel/pharmacology , Paclitaxel/therapeutic use , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Tubulin Modulators/therapeutic useABSTRACT
Epothilones are a class of 16-membered macrolide compounds targeting microtubules. They have good anticancer activity and their mechanism of action is similar to that of paclitaxel. Epothilones are also highly active against cancer cells that are resistant to paclitaxel and other anticancer drugs. They have good water solubility, simple structure, and are relatively easy to totally synthesize and or semi-synthesize. These results immediately attracted great interest and research enthusiasm from pharmaceutical companies and academia. Herein, the various synthetic methods of epothilone B and its anticancer activity were summarized and analyzed.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Epothilones/chemical synthesis , Epothilones/pharmacology , Neoplasms/drug therapy , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Epothilones/chemistry , Humans , Molecular Structure , Neoplasms/pathology , Structure-Activity RelationshipABSTRACT
Epothilone is a newly developed antitumor drug; its antitumor principle is to stop the cell cycle by binding to tubulin in tumor cells, promoting tubulin polymerization, inhibiting depolymerization of microtubules, and ultimately inducing apoptosis. There are many analogs of epothilone, such as epothilone B, epothilone D, ixabepilone, sagopilone, 21-amino-epothilone B and KOS-1584. Herein, the synthesis and antitumor activity of epothilones B and D were summed up. The antitumor activity of epothilone analogs was also compared. Synthesis of epothilone and its analogs is more complex, and choosing the proper synthetic method is very important. Moreover, these compounds have obvious antitumor effect. The epothilone and its analogs will continue to play an important role in the future treatment of tumors.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Epothilones/chemical synthesis , Epothilones/pharmacology , Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemistry , Drug Design , Epothilones/chemistry , Humans , Neoplasms/metabolism , Neoplasms/pathology , Structure-Activity Relationship , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
The synthesis and biological evaluation of a series of 12,13-aziridinyl epothilone B analogues is described. These compounds were accessed by a practical, general process that involved a 12,13-olefinic methyl ketone as a starting material obtained by ozonolytic cleavage of epothilone B followed by tungsten-induced deoxygenation of the epoxide moiety. The attachment of the aziridine structural motif was achieved by application of the Ess-Kürti-Falck aziridination, while the heterocyclic side chains were introduced via stereoselective phosphonate-based olefinations. In order to ensure high (E) selectivities for the latter reaction for electron-rich heterocycles, it became necessary to develop and apply an unprecedented modification of the venerable Horner-Wadsworth-Emmons reaction, employing 2-fluoroethoxyphosphonates that may prove to be of general value in organic synthesis. These studies resulted in the discovery of some of the most potent epothilones reported to date. Equipped with functional groups to accommodate modern drug delivery technologies, some of these compounds exhibited picomolar potencies that qualify them as payloads for antibody drug conjugates (ADCs), while a number of them revealed impressive activities against drug resistant human cancer cells, making them desirable for potential medical applications.
Subject(s)
Alkenes/pharmacology , Antineoplastic Agents/pharmacology , Aziridines/pharmacology , Drug Design , Epothilones/pharmacology , Ketones/pharmacology , Organophosphonates/pharmacology , Alkenes/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aziridines/chemical synthesis , Aziridines/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Epothilones/chemical synthesis , Epothilones/chemistry , Humans , Hydrocarbons, Aromatic/chemistry , Hydrocarbons, Aromatic/pharmacology , Ketones/chemistry , Molecular Structure , Organophosphonates/chemistry , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Here, a concise and highly convergent synthesis of epothiloneâ 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 ß-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.
Subject(s)
Epothilones/chemical synthesis , Boron/chemistry , Catalysis , Crystallography, X-Ray , Epothilones/chemistry , Lactones/chemistry , Magnesium/chemistry , Molecular Conformation , Stereoisomerism , Zinc/chemistryABSTRACT
12-Aza-epothilones (azathilones) incorporating quinoline side chains and bearing different N12-substituents have been synthesized via highly efficient RCM-based macrocyclizations. Quinoline-based azathilones with the side chain N-atom in the meta-position to the C15 atom in the macrocycle are highly potent inhibitors of cancer cell growth in vitro. In contrast, shifting the quinoline nitrogen to the position para to C15 leads to a ca. 1000-fold loss in potency. Likewise, the desaturation of the C9-C10 bond in the macrocycle to an E double bond produces a substantial reduction in antiproliferative activity. This is in stark contrast to the effect exerted by the same modification in the natural epothilone macrocycle. The conformation of a representative azathilone bound to α/ß-tubulin heterodimers was determined based on TR-NOE measurements and a model for the posture of the compound in its binding site on ß-tubulin was deduced through a combination of STD measurements and CORCEMA-ST calculations. The tubulin-bound, bioactive conformation of azathilones was found to be overall similar to that of epothilones A and B.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Epothilones/chemical synthesis , Epothilones/pharmacology , Tubulin/metabolism , A549 Cells , Antineoplastic Agents/chemistry , Binding Sites , Cell Proliferation/drug effects , Cell Survival/drug effects , Cyclization , Drug Screening Assays, Antitumor , Epothilones/chemistry , Hep G2 Cells , Humans , Models, Molecular , Molecular Structure , Protein Binding , Protein Conformation , Tubulin/chemistryABSTRACT
A second-generation synthesis of the C(1)-C(9) fragment of the epothilones is reported. The key tandem intramolecular silylformylation/crotylsilylation/"aprotic" Tamao oxidation sequence has been redeveloped as a stepwise intermolecular variant, allowing excellent levels of diastereoselectivity in the crotylation step and proceeds in 50% overall yield on gram scale. An improved synthesis of the homopropargyl alcohol starting material is also described, which proceeds in four steps and >99% ee from inexpensive starting materials and is amenable to multigram scales.
Subject(s)
Epothilones/chemical synthesis , Alcohols/chemistry , Epothilones/chemistry , Molecular Structure , Oxidation-Reduction , StereoisomerismABSTRACT
The stabilization of microtubules using epothilones represents a novel mechanism of action to treat Alzheimer's disease. Epothilone D is one such microtubule-stabilizing drug that has been investigated by Bristol-Myers Squibb. An important step in the development process was the synthesis of a stable isotope-labeled analog for use in bioanalytical assays to accurately quantify the concentration of the drug in biological samples. A novel synthetic route to stable isotope-labeled epothilone D is described. The synthetic route was based on a strategy to degrade epothilone B and then use that key intermediate to reconstruct stable isotope-labeled epothilone D. Epothilone B was treated with potassium osmate and sodium periodate. The thiazole moiety in epothilone B was efficiently cleaved to give (1S,3S,7S,10R,11S,12S,16R)-3-acetyl-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione. The epoxide in the macrocyclic ring of that intermediate was cleanly removed by treatment with tungsten hexachloride and n-butyllithium to give the corresponding olefin (4S,7R,8S,9S,16S,Z)-16-acetyl-4,8-dihydroxy-5,5,7,9,13-pentamethyloxacyclohexadec-13-ene-2,6-dione. Bis(triethylsilyl) protection produced (4S,7R,8S,9S,16S,Z)-16-acetyl-5,5,7,9,13-pentamethyl-4,8-bis(triethylsilyloxy)-oxacyclohexadec-13-ene-2,6-dione. This intermediate was coupled to a stable isotope-labeled thiazole using a Wittig reaction as the key step to provide (13)C5, (15)N-labeled epothilone D. In summary, the synthesis was completed in nine total steps, only six of which involved isotopically labeled reagents. A total of 168 mg of (13)C5, (15)N-labeled epothilone D was prepared in an 8% overall yield from (13)C2, (15)N-labeled thioacetamide and (13)C3-labeled ethyl bromopyruvate.
Subject(s)
Carbon Isotopes/chemical synthesis , Carbon Isotopes/isolation & purification , Epothilones/chemical synthesis , Isotope Labeling/methods , Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/isolation & purification , Drug StabilityABSTRACT
Modulators of microtubule dynamics have received increasing attention because of their potential to stop cancer growth. Although it belongs to the category of complex protein-protein interactions (PPIs), which are generally considered difficult to modulate through small molecules, the use of microtubule is considered a well-validated target. There are a number of bioactive natural products and related compounds that are currently in use as drugs or in clinical trials as next generation anti-cancer agents. The present review article is focused on two such bioactive natural products, epothilone and halichondrin B, and covers some of the key papers published after 2005 that outline various synthetic approaches to obtain next generation structural analogs as well as the synthesis of hybrid compounds.
Subject(s)
Biological Products/pharmacology , Epothilones/pharmacology , Ethers, Cyclic/pharmacology , Macrolides/pharmacology , Tubulin Modulators/pharmacology , Tubulin/metabolism , Animals , Biological Products/chemical synthesis , Biological Products/chemistry , Epothilones/chemical synthesis , Epothilones/chemistry , Ethers, Cyclic/chemical synthesis , Ethers, Cyclic/chemistry , Humans , Macrolides/chemical synthesis , Macrolides/chemistry , Molecular Structure , Structure-Activity Relationship , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistryABSTRACT
Epothilones are natural compounds isolated from a myxobacterium at the beginning of the 1990s, and showed a remarkable anti-neoplastic activity. They act through the same mechanism of action of paclitaxel, by stabilizing microtubules and inducing apoptosis. Although, their chemical structure, simpler than taxanes, makes them more suitable for derivatization. Their interesting pharmacokinetic and bioavailabilty profiles, and the activity against paclitaxel-resistant cell lines make them interesting therapeutic agents. Here a brief historical perspective of epothilones is presented, since their isolation, the identification of their mechanism of action and activity, to the recent clinical trials.
Subject(s)
Antineoplastic Agents/chemical synthesis , Epothilones/chemical synthesis , Microtubules/drug effects , Mitosis/drug effects , Tubulin Modulators/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Line, Tumor , Clinical Trials as Topic , Drug Design , Epothilones/chemistry , Epothilones/pharmacology , Humans , Molecular Docking Simulation , Neoplasms/chemistry , Neoplasms/drug therapy , Neoplasms/pathology , Paclitaxel/chemistry , Paclitaxel/pharmacology , Protein Binding , Structure-Activity Relationship , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
The epothilones, including epothilones B and D, are macrocyclic lactones, which have potent cytotoxicities and promote the polymerization of tubulin to mictotubules by binding to and stabilizing the tubulin polymer. They have a very similar mechanism of action to paclitaxel (Taxol®). The determination of the microtubule-binding conformation of the epothilones is an important piece of information in designing improved analogs for possible clinical use, and internuclear distance information that will assist the determination of this conformation can be obtained by rotational echo double resonance (REDOR) NMR studies of microtubule-bound epothilones with appropriate stable isotope labels. Analogs of epothilone B and epothilone D with [(2) H3 ] and [(19) F] labels were prepared from an advanced precursor for potential use in REDOR NMR studies to determine internuclear distances in tubulin-bound ligand.
Subject(s)
Deuterium/chemistry , Epothilones/chemical synthesis , Isotope Labeling , Tubulin Modulators/chemical synthesis , Cell Line, Tumor , Epothilones/chemistry , Epothilones/pharmacology , Humans , Protein Binding , Tubulin/metabolism , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
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.
Subject(s)
Aldehydes/chemistry , Epothilones/chemical synthesis , Macrolides/chemical synthesis , Chromium/chemistry , Epothilones/chemistry , Macrolides/chemistryABSTRACT
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.
Subject(s)
Breast Neoplasms/drug therapy , Epothilones , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Combinatorial Chemistry Techniques , Computer Simulation , Crystallography, X-Ray , Epothilones/chemical synthesis , Epothilones/chemistry , Epothilones/pharmacology , Female , Humans , Inhibitory Concentration 50 , Models, Biological , Molecular StructureABSTRACT
The first broadly applicable set of protocols for efficient Z-selective formation of macrocyclic disubstituted alkenes through catalytic ring-closing metathesis (RCM) is described. Cyclizations are performed with 1.2-7.5 mol% of a Mo- or W-based monoaryloxide pyrrolide (MAP) complex at 22 °C and proceed to complete conversion typically within two hours. Utility is demonstrated by synthesis of representative macrocyclic alkenes, such as natural products yuzu lactone (13-membered ring: 73% Z) epilachnene (15-membered ring: 91% Z), ambrettolide (17-membered ring: 91% Z), an advanced precursor to epothilones C and A (16-membered ring: up to 97% Z), and nakadomarin A (15-membered ring: up to 97% Z). We show that catalytic Z-selective cyclizations can be performed efficiently on gram-scale with complex molecule starting materials and catalysts that can be handled in air. We elucidate several critical principles of the catalytic protocol: 1) The complementary nature of the Mo catalysts, which deliver high activity but can be more prone towards engendering post-RCM stereoisomerization, versus W variants, which furnish lower activity but are less inclined to cause loss of kinetic Z selectivity. 2) Reaction time is critical to retaining kinetic Z selectivity not only with MAP species but with the widely used Mo bis(hexafluoro-tert-butoxide) complex as well. 3) Polycyclic structures can be accessed without significant isomerization at the existing Z alkenes within the molecule.
Subject(s)
Alkaloids/chemical synthesis , Biological Products/chemical synthesis , Bridged-Ring Compounds/chemical synthesis , Carbolines/chemical synthesis , Cycloparaffins/chemical synthesis , Epothilones/chemical synthesis , Lactones/chemical synthesis , Macrocyclic Compounds/chemical synthesis , Molybdenum/chemistry , Ruthenium/chemistry , Alkaloids/chemistry , Biological Products/chemistry , Bridged-Ring Compounds/chemistry , Carbolines/chemistry , Catalysis , Cyclization , Cycloparaffins/chemistry , Epothilones/chemistry , Kinetics , Lactones/chemistry , Macrocyclic Compounds/chemistry , Molecular Structure , StereoisomerismSubject(s)
Alkenes/chemistry , Coordination Complexes/chemistry , Imines/chemistry , Macrocyclic Compounds/chemistry , Molybdenum/chemistry , Alkenes/chemical synthesis , Catalysis , Epothilones/chemical synthesis , Epothilones/chemistry , Ligands , Macrocyclic Compounds/chemical synthesis , Oxides/chemistry , TemperatureABSTRACT
An efficient total synthesis of (-)-epothilone B has been achieved in ca. 8% yield over 11 steps from 9 (or 10 steps from 7/8), which features a bissiloxane-tethered ring closing metathesis reaction to approach the trisubstituted (Z) double bond and forms a new basis for further development of an industrial process for epothilone B and ixabepilone.
Subject(s)
Epothilones/chemical synthesis , Cyclization , Epothilones/chemistry , Molecular Structure , StereoisomerismABSTRACT
An efficient synthesis of the C(1)-C(9) fragment of fludelone has been developed. The key step is a tandem silylformylation-crotylsilylation/Tamao oxidation sequence that establishes the C(5) ketone, the C(6), C(7), and C(8) stereocenters, and the C(9) alkene in a single operation from a readily accessed starting material. The stereochemical outcome at C(6) depends critically on the development of an "aprotic" Tamao oxidation, which leads to a reversal in the intrinsic diastereoselectivity observed using "standard" Tamao oxidation conditions.