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K C Nicolaou - One of the best experts on this subject based on the ideXlab platform.
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12 13 aziridinyl Epothilones stereoselective synthesis of trisubstituted olefinic bonds from methyl ketones and heteroaromatic phosphonates and design synthesis and biological evaluation of potent antitumor agents
Journal of the American Chemical Society, 2017Co-Authors: K C Nicolaou, Ernest Hamel, Derek Rhoades, Yanping Wang, Ruoli Bai, Monette Aujay, Joseph Sandoval, Julia GavrilyukAbstract: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–Kurti–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 ...
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12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents
2017Co-Authors: K C Nicolaou, Ernest Hamel, Derek Rhoades, Yanping Wang, Ruoli Bai, Monette Aujay, Joseph Sandoval, Julia GavrilyukAbstract: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
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synthesis and biological evaluation of novel Epothilone b side chain analogues
ChemMedChem, 2015Co-Authors: K C Nicolaou, Derek Rhoades, Yanping Wang, Sotirios Totokotsopoulos, Ernest HamelAbstract:: The design, synthesis, and biological evaluation of a series of Epothilone analogues with novel side chains equipped with an amino group are described. Their design facilitates potential conjugation to selective drug delivery systems such as antibodies. Their synthesis proceeded efficiently via Stille coupling of a readily available vinyl iodide and heterocyclic stannanes. Cytotoxicity studies and tubulin binding assays revealed two of these analogues to be more potent than Epothilones A-D and the anticancer agent ixabepilone, currently in clinical use.
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chemical synthesis and biological evaluation of cis and trans 12 13 cyclopropyl and 12 13 cyclobutyl Epothilones and related pyridine side chain analogues
Journal of the American Chemical Society, 2001Co-Authors: Andreas Ritzen, Kenji Namoto, K C Nicolaou, Trond Ulven, Mitsuru Shoji, Gina DamicoAbstract:The design, chemical synthesis, and biological evaluation of a series of cyclopropyl and cyclobutyl Epothilone analogues (3−12, Figure 1) are described. The synthetic strategies toward these Epothilones involved a Nozaki−Hiyama−Kishi coupling to form the C15−C16 carbon−carbon bond, an aldol reaction to construct the C6−C7 carbon−carbon bond, and a Yamaguchi macrolactonization to complete the required skeletal framework. Biological studies with the synthesized compounds led to the identification of Epothilone analogues 3, 4, 7, 8, 9, and 11 as potent tubulin polymerization promoters and cytotoxic agents with (12R,13S,15S)-cyclopropyl 5-methylpyridine Epothilone A (11) as the most powerful compound whose potencies (e.g. IC50 = 0.6 nM against the 1A9 ovarian carcinoma cell line) approach those of Epothilone B. These investigations led to a number of important structure−activity relationships, including the conclusion that neither the epoxide nor the stereochemistry at C12 are essential, while the stereochemi...
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total synthesis of 16 desmethylEpothilone b Epothilone b10 Epothilone f and related side chain modified Epothilone b analogues
Chemistry: A European Journal, 2000Co-Authors: K C Nicolaou, Birgit Bollbuck, Paul N King, David Hepworth, Raymond M V Finlay, Rita Scarpelli, Mariette M Pereira, Antony Bigot, Barbara Werschkun, Nicolas WinssingerAbstract:The macrolactonization-based strategy for the total synthesis of Epothilones has been streamlined and improved to a high level of efficiency and stereoselectivity. This strategy has been applied to the construction of vinyl iodide 19 which served as a common intermediate for the synthesis of a series of natural and designed Epothilones including an Epothilone B10 (3), Epothilone F (5), 16-desmethylEpothilone B (14), pyridine Epothilones 57 a–57 g, dimeric Epothilones 59 and 61, and benzenoid Epothilones 63 a–63 g.
Ernest Hamel - One of the best experts on this subject based on the ideXlab platform.
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12 13 aziridinyl Epothilones stereoselective synthesis of trisubstituted olefinic bonds from methyl ketones and heteroaromatic phosphonates and design synthesis and biological evaluation of potent antitumor agents
Journal of the American Chemical Society, 2017Co-Authors: K C Nicolaou, Ernest Hamel, Derek Rhoades, Yanping Wang, Ruoli Bai, Monette Aujay, Joseph Sandoval, Julia GavrilyukAbstract: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–Kurti–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 ...
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12,13-Aziridinyl Epothilones. Stereoselective Synthesis of Trisubstituted Olefinic Bonds from Methyl Ketones and Heteroaromatic Phosphonates and Design, Synthesis, and Biological Evaluation of Potent Antitumor Agents
2017Co-Authors: K C Nicolaou, Ernest Hamel, Derek Rhoades, Yanping Wang, Ruoli Bai, Monette Aujay, Joseph Sandoval, Julia GavrilyukAbstract: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
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synthesis and biological evaluation of novel Epothilone b side chain analogues
ChemMedChem, 2015Co-Authors: K C Nicolaou, Derek Rhoades, Yanping Wang, Sotirios Totokotsopoulos, Ernest HamelAbstract:: The design, synthesis, and biological evaluation of a series of Epothilone analogues with novel side chains equipped with an amino group are described. Their design facilitates potential conjugation to selective drug delivery systems such as antibodies. Their synthesis proceeded efficiently via Stille coupling of a readily available vinyl iodide and heterocyclic stannanes. Cytotoxicity studies and tubulin binding assays revealed two of these analogues to be more potent than Epothilones A-D and the anticancer agent ixabepilone, currently in clinical use.
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activities of the microtubule stabilizing agents Epothilones a and b with purified tubulin and in cells resistant to paclitaxel taxol
Journal of Biological Chemistry, 1997Co-Authors: Richard J Kowalski, Paraskevi Giannakakou, Ernest HamelAbstract:Epothilones A and B, natural products with minimal structural analogy to taxoids, have effects similar to those of paclitaxel (Taxol ® ) in cultured cells and on microtubule protein, but differ from paclitaxel in retaining activity in multidrug-resistant cells. We examined interactions of the Epothilones with purified tubulin and additional cell lines, including a paclitaxel-resistant ovarian carcinoma line with an altered b-tubulin. The Epothilones, like paclitaxel, induced tubulin to form microtubules at low temperatures and without GTP and/or microtubule-associated proteins. The Epothilones are competitive inhibitors of the binding of [ 3 H]paclitaxel to tubulin polymers. The apparent Ki values for Epothilones A and B were 1.4 and 0.7 mM by Hanes analysis and 0.6 and 0.4 mM by Dixon analysis. In the paclitaxel-sensitive human cell lines we examined, Epothilone B had greater antiproliferative activity than Epothilone A or paclitaxel, while Epothilone A was usually less active than paclitaxel. A multidrug-resistant colon carcinoma line and the paclitaxel-resistant ovarian line retained sensitivity to the Epothilones. With Potorous tridactylis kidney epithelial (PtK2) cells examined by indirect immunofluorescence, microtubule bundles appeared more rapidly following Epothilone B treatment, and there were different proportions of various mitotic aberrations following treatment with different drugs.
Karl-heinz Altmann - One of the best experts on this subject based on the ideXlab platform.
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On the Importance of the Thiazole Nitrogen in Epothilones: Semisynthesis and Microtubule-Binding Affinity of Deaza-Epothilone C
Chemistry: A European Journal, 2020Co-Authors: Adriana Edenharter, Lucie Ryckewaert, Daniela Cintulová, Juan Estévez-gallego, José Fernando Díaz, Karl-heinz AltmannAbstract:Deaza-Epothilone C, which incorporates a thiophene moiety in place of the thiazole heterocycle in the natural Epothilone side chain, has been prepared by semisynthesis from Epothilone A, in order to assess the contribution of the thiazole nitrogen to microtubule binding. The synthesis was based on the esterification of a known Epothilone A-derived carboxylic acid fragment and a fully synthetic alcohol building block incorporating the modified side chain segment and subsequent ring-closure by ring-closing olefin metathesis. The latter proceeded with unfavorable selectivity and in low yield. Distinct differences in chemical behavior were unveiled between the thiophene-derived advanced intermediates and what has been reported for the corresponding thiazole-based congeners. Compared to natural Epothilone C, the free energy of binding of deaza-Epothilone C to microtubules was reduced by ca. 1 kcal/mol or less, thus indicating a distinct but non-decisive role of the thiazole nitrogen in the interaction of Epothilones with the tubulin/microtubule system. In contrast to natural Epothilone C, deaza-Epothilone C was devoid of antiproliferative activity in vitro up to a concentration of 10 μM, presumably due to an insufficient stability in the cell culture medium.
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Synthesis, Biological Profiling and Determination of the Tubulin-Bound Conformation of 12-Aza-Epothilones (Azathilones)
MDPI AG, 2016Co-Authors: Andrea Jantsch, Fernando J Diaz, Lidia Nieto, Jürg Gertsch, Javier Rodríguez-salarichs, Ruth Matesanz, Jesús Jiménez-barbero, Ángeles Canales, Karl-heinz AltmannAbstract: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/β-tubulin heterodimers was determined based on TR-NOE measurements and a model for the posture of the compound in its binding site on β-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
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diversity through semisynthesis the chemistry and biological activity of semisynthetic Epothilone derivatives
ChemInform, 2011Co-Authors: Karl-heinz Altmann, Fabienne Z. Gaugaz, Raphael SchiessAbstract:Epothilones are myxobacterial natural products that inhibit human cancer cell growth through the stabil- ization of cellular microtubules (i.e., a "taxol-like" mech- anism of action). They have proven to be highly productive lead structures for anticancer drug discovery, with at least seven Epothilone-type agents having entered clinical trials in humans over the last several years. SAR studies on epothil- ones have included a large number of fully synthetic ana- logs and semisynthetic derivatives. Previous reviews on the chemistryandbiologyofEpothiloneshavemostlyfocusedon analogs thatwereobtainedbydenovochemical synthesis.In contrast, the current review provides a comprehensive over- view on the chemical transformations that have been investi- gatedforthemajorEpothilonesAandBasstartingmaterials, and it discusses the biological activity of the resulting prod- ucts. Many semisynthetic Epothilone derivatives have been found to exhibit potent effects on human cancer cell growth and several of these have been advanced to the stage of clini-
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Diversity through semisynthesis: the chemistry and biological activity of semisynthetic Epothilone derivatives
Molecular Diversity, 2011Co-Authors: Karl-heinz Altmann, Fabienne Z. Gaugaz, Raphael SchiessAbstract:Epothilones are myxobacterial natural products that inhibit human cancer cell growth through the stabilization of cellular microtubules (i.e., a “taxol-like” mechanism of action). They have proven to be highly productive lead structures for anticancer drug discovery, with at least seven Epothilone-type agents having entered clinical trials in humans over the last several years. SAR studies on Epothilones have included a large number of fully synthetic analogs and semisynthetic derivatives. Previous reviews on the chemistry and biology of Epothilones have mostly focused on analogs that were obtained by de novo chemical synthesis. In contrast, the current review provides a comprehensive overview on the chemical transformations that have been investigated for the major Epothilones A and B as starting materials, and it discusses the biological activity of the resulting products. Many semisynthetic Epothilone derivatives have been found to exhibit potent effects on human cancer cell growth and several of these have been advanced to the stage of clinical development. This includes the Epothilone B lactam ixabepilone (Ixempra^®, which has been approved by the FDA for the treatment of advanced and metastatic breast cancer.
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design synthesis and biological properties of highly potent Epothilone b analogues
Angewandte Chemie, 2003Co-Authors: Gerasimos A Rassias, Mali V Reddy, Karl-heinz Altmann, Kyriacos C Nicolaou, Prakash Kumar Sasmal, Markus WartmannAbstract:Owing to their potent cytotoxicity against tumor cells, including taxol (paclitaxel)-resistant cell lines, the Epothilones (for example, Epothilone A (1) and Epothilone B (2)) continue to be the focus of intense chemical, biological, and clinical research efforts around the world. 3] Following the findings that cyclopropane-, methylsulfanylthiazole-, and pyridine-containing Epothilone B derivatives (e.g. 3 and 5,) exhibit outstanding biological profiles as potential antitumor agents, we directed our attention toward the synthesis and evaluation of a small designed library of Epothilone B analogues whose members are characterized by such structural motifs. Herein we report the details of these synthetic and biological investigations, which culminated in the discovery of 12,13-cis-cyclopropane methylsulfanyl Epothilone B (4) as an extremely potent Epothilone B analogue. The design of the present focused Epothilone library was based on the current knowledge of structure–activity relationships (SAR), specifically the facts that: 1) Epothilone B (2) is considerably more potent than Epothilone A (1), 2) a methylsulfanyl replacement for the methyl group on the thiazole moiety enhances the potency, 3) a heterocycle (e.g. pyridine) replacement for the thiazole ring needs to maintain the proper position (adjacent to the point of
Gerhard Höfle - One of the best experts on this subject based on the ideXlab platform.
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discovery and development of the Epothilones a novel class of antineoplastic drugs
Drugs in R & D, 2008Co-Authors: Hans Reichenbach, Gerhard HöfleAbstract:The Epothilones are a novel class of antineoplastic agents possessing antitubulin activity. The compounds were originally identified as secondary metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum. Two major compounds, Epothilone A and Epothilone B, were purified from the S. cellulosum strain So ce90 and their structures were identified as 16-member macrolides. Initial screening with these compounds revealed a very narrow and selective antifungal activity against the zygomycete, Mucor hiemalis. In addition, strong cytotoxic activity against eukaryotic cells, mouse L929 fibroblasts and human T-24 bladder carcinoma cells was observed. Subsequent studies revealed that Epothilones induce tubulin polymerization and enhance microtubule stability. Epothilone-induced stabilisation of microtubules was shown to cause arrest at the G2/M transition of the cell cycle and apoptosis. The compounds are active against cancer cells that have developed resistance to taxanes as a result of acquisition of β-tubulin overexpression or mutations and against multidrug-resistant cells that overexpress P-glycoprotein or multidrug resistance-associated protein. Thus, Epothilones represent a new class of antimicrotubule agents with low susceptibility to key tumour resistance mechanisms. More recently, a range of synthetic and semisynthetic Epothilone analogues have been produced to further improve the adverse effect profile (or therapeutic window) and to maximize pharmacokinetic and antitumour properties. Various Epothilone analogues have demonstrated activity against many tumour types in preclinical studies and several compounds have been and still are being evaluated in clinical trials. This article reviews the identification and early molecular characterization of the Epothilones, which has provided insight into the mode of action of these novel antitumour agents in vivo.
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synthesis of Epothilone 16 17 alkyne analogs by replacement of the c13 c15 o ring segment of natural Epothilone c
European Journal of Organic Chemistry, 2003Co-Authors: Usama Karama, Gerhard HöfleAbstract:Ring-opening cross metathesis of Epothilone C (4a) with ethylene, followed by silyl protection and ester hydrolysis, yielded an eastern ring segment C1−C12 as the carboxylic acid 10. Separately, a western ring segment 12 carrying a C16−C17 triple bond was synthesized and coupled with 10 to form the ester 13. Ring closure by olefin metathesis, deprotection, and then epoxidation, gave the 16,17-alkyne analogs (14b, 3b) of Epothilone C and Epothilone A. The identity of 3b was proven by hydrogenation to (16Z)-Epothilone A8 (17) and comparison with an authentic sample prepared from natural Epothilone A8 (18). The biological activity of the new Epothilones was determined. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
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Semisynthesis and degradation of the tubulin inhibitors Epothilone and tubulysin
Pure and Applied Chemistry, 2003Co-Authors: Gerhard Höfle, Florenz Sasse, Usama Karama, Nicole Glaser, Thomas Leibold, Heinrich SteinmetzAbstract:The structure-activity relationships of Epothilones indicate that major modifica- tions are only tolerated in the western ring segment. In particular, C2 methyl of the thiazole ring appears to be most flexible. Its broad modification started from Epothilone F, which was obtained from natural Epothilone B by hydroxylation via the N-oxide. Some of the prepared derivatives exhibit improved esterase stability in addition to high cytotoxic activity. For these and other favorable properties, amine (BMS-310705) was recently introduced in clinical trials. In an alternative approach, modified side chains were introduced by replacement of the C12,C15 ring segment via ring-opening olefin metathesis (ROM) of Epothilone C in the pres- ence of ethylene to 12,13-seco-Epothilone C, introduction of a synthetic building block fol- lowed by ring-closing olefin metathesis (RCM), and epoxidation to the 16-alkyne analog of Epothilone A. The structure of the tetrapeptide tubulysin D was confirmed by total hydrolysis to N-methyl D-pipecolic acid, L-isoleucine, tubuvaline (Tuv), tubuphenylalanine (Tup), formaldehyde, and 3-methylbutyric acid. Mild acidic hydrolysis to cyclo-tubulysin and oxidative degradation to L-valine allowed the assignment of the stereocenters of Tuv, hydrazi- nolysis, and comparison with synthetic reference samples to that of Tup. The absolute con- figuration of tubulysin D is: (R)-Mep, (2S,3S)-Ile, (1'R,3'R)-Tuv, and (2S,4R)-Tup.
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new natural Epothilones from sorangium cellulosum strains so ce90 b2 and so ce90 d13 isolation structure elucidation and sar studies
Journal of Natural Products, 2001Co-Authors: Ingo Hardt, Florenz Sasse, Heinrich Steinmetz, Klaus Gerth, Hans Reichenbach, Gerhard HöfleAbstract:In addition to Epothilones A (1) and B (2), 37 natural Epothilone variants and Epothilone-related compounds were isolated from the culture broth of a 700 L fermentation of Sorangium cellulosum, strain So ce90/B2. Of these, only the 12,13-desoxyEpothilones, Epothilone C (14) and D (15), were produced in significant amounts (3−6 mg/L); the 21-hydroxy derivatives and Epothilones E (3) and F (4), in low and variable amounts due to further degradation by the producing organism. Most of the other Epothilone variants were produced only in 1−100 μg/L amounts. The new compounds are very similar in structure to the parent compounds 1, 2 and 14, 15 and are presumably the result of the imperfect selectivity of the biosynthetic enzymes for acetate and propionate. Further, Epothilones containing an oxazole moiety (10−13) in the side chain instead of a thiazole as well as ring-expanded 18-membered macrolides, Epothilones I (30−35), and a ring contracted 14-membered macrolide, Epothilone K (36), were found as very minor ...
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new natural Epothilones from sorangium cellulosum strains so ce90 b2 and so ce90 d13 isolation structure elucidation and sar studies
Journal of Natural Products, 2001Co-Authors: Ingo Hardt, Florenz Sasse, Heinrich Steinmetz, Klaus Gerth, Hans Reichenbach, Gerhard HöfleAbstract:In addition to Epothilones A (1) and B (2), 37 natural Epothilone variants and Epothilone-related compounds were isolated from the culture broth of a 700 L fermentation of Sorangium cellulosum, strain So ce90/B2. Of these, only the 12,13-desoxyEpothilones, Epothilone C (14) and D (15), were produced in significant amounts (3-6 mg/L); the 21-hydroxy derivatives and Epothilones E (3) and F (4), in low and variable amounts due to further degradation by the producing organism. Most of the other Epothilone variants were produced only in 1-100 microg/L amounts. The new compounds are very similar in structure to the parent compounds 1, 2 and 14, 15 and are presumably the result of the imperfect selectivity of the biosynthetic enzymes for acetate and propionate. Further, Epothilones containing an oxazole moiety (10-13) in the side chain instead of a thiazole as well as ring-expanded 18-membered macrolides, Epothilones I (30-35), and a ring contracted 14-membered macrolide, Epothilone K (36), were found as very minor metabolites. The mutant strain, So ce90/D13, instead of macrolactones, produced short-chain carboxylic acids 40, 41, and 42 bearing the characteristic thiazole side chain. The structures of the new Epothilones were elucidated on the basis of comprehensive NMR and MS data. The new Epothilone variants were tested in a cytotoxicity assay with mouse fibroblasts (cell line L929), and structure-activity relationships were established. Several new natural Epothilones showed activity comparable to 1 and 2, but in no case exceeded that of 2.
Gregory D Vite - One of the best experts on this subject based on the ideXlab platform.
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Preclinical discovery of ixabepilone, a highly active antineoplastic agent
Cancer Chemotherapy and Pharmacology, 2008Co-Authors: Francis Y. F. Lee, Richard Smykla, Robert M Borzilleri, Craig R Fairchild, Amrita Kamath, Robert Kramer, Gregory D ViteAbstract:The Epothilones and their analogs constitute a novel class of antineoplastic agents, produced by the myxobacterium Sorangium cellulosum . These antimicrotubule agents act in a similar manner to taxanes, stabilizing microtubules and resulting in arrested tumor cell division and apoptosis. Unlike taxanes, however, Epothilones and their analogs are macrolide antibiotics, with a distinct tubulin binding mode and reduced susceptibility to a range of common tumor resistance mechanisms that limit the effectiveness of taxanes and anthracyclines. While natural Epothilones A and B show potent antineoplastic activity in vitro, these effects were not seen in preclinical in vivo models due to their poor metabolic stability and unfavorable pharmacokinetics. A range of Epothilone analogs was synthesized, therefore, with the aim of identifying those with more favorable characteristics. Here, we describe the preclinical characterization and selection of ixabepilone, a semi-synthetic Epothilone B analog, among many other Epothilone analogs. Ixabepilone demonstrated superior preclinical characteristics, including high metabolic stability, low plasma protein binding and low susceptibility to multidrug resistance protein-mediated efflux, all of which were predictive of potent in vivo cell-killing activity. Ixabepilone also demonstrated in vivo antitumor activity in a range of human tumor models, several of which displayed resistance to commonly used agents such as anthracyclines and taxanes. These favorable preclinical characteristics have since translated to the clinic. Ixabepilone has shown promising phase II clinical efficacy and acceptable tolerability in a wide range of cancers, including heavily pretreated and drug-resistant tumors. Based on these results, a randomized phase III trial was conducted in anthracycline-pretreated or resistant and taxane-resistant metastatic breast cancer to evaluate ixabepilone in combination with capecitabine. Ixabepilone combination therapy showed significantly superior progression-free survival and tumor responses over capecitabine alone.
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synthesis and biological activity of novel Epothilone aziridines
Organic Letters, 2001Co-Authors: Alicia Regueiroren, Robert M Borzilleri, Xiaoping Zheng, James A Johnson, Craig R Fairchild, Soonghoon Kim, Francis Y Lee, Byron H Long, Gregory D ViteAbstract:[reaction: see text]. A series of 12alpha,13alpha-aziridinyl Epothilone derivatives were synthesized in an efficient manner from Epothilone A. The final semisynthetic route involves a formal double-inversion of stereochemistry at both the C12 and C13 positions. All aziridine analogues were tested for effects on tubulin binding polymerization and cytotoxicity. The results indicate that the aziridine moiety is a viable isosteric replacement for the epoxide in the case of Epothilones.
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a novel application of a pd 0 catalyzed nucleophilic substitution reaction to the regio and stereoselective synthesis of lactam analogues of the Epothilone natural products
Journal of the American Chemical Society, 2000Co-Authors: Robert M Borzilleri, Xiaoping Zheng, Robert J Schmidt, James A Johnson, John D Dimarco, Craig R Fairchild, Jack Z Gougoutas, And Byron Long, Gregory D ViteAbstract:Several lactam analogues of the Epothilones were prepared using a concise semisynthetic approach starting with the unprotected natural products. Highlighted in this strategy is a novel regio- and stereoselective Pd(0)-catalyzed azidation reaction of a macrocyclic lactone. Subsequent reduction and macrolactamization of the resulting azide acid intermediates provided the desired macrolactams in satisfactory overall yields. The entire three-step sequence was streamlined into a “one-pot” process for the Epothilone B-lactam, BMS-247550, which is currently undergoing phase I clinical trials. An initial total synthesis route to prepare the lactam analogue of Epothilone C was completed and compared to the more direct semisynthesis approach. All of the lactam analogues were evaluated in vitro and the results are discussed.
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synthesis structure proof and biological activity of Epothilone cyclopropanes
Organic Letters, 2000Co-Authors: James A Johnson, John D Dimarco, Jack Z Gougoutas, Soonghoon Kim, Francis Y Lee, Byron H Long, Marc Bifano, Craig Fairchild, John S Tokarski, Gregory D ViteAbstract:[structure--see text] A semisynthetic route to Epothilone cyclopropanes from Epothilones A and B is described. Of significance, the deoxygenation of the 12, 13-epoxide to give the corresponding olefin was achieved with high efficiency. The title compounds (8, 9) were active in both tubulin polymerization and cytotoxicity assays, which is in direct contrast to a previously published report. These results provide further evidence that the role of the 12,13-epoxide of Epothilones is largely conformational and argue against some of the current pharmacophore models.