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K C Nicolaou - One of the best experts on this subject based on the ideXlab platform.

  • 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, 2001
    Co-Authors: K C Nicolaou, Kenji Namoto, Andreas Ritzen, Trond Ulven, Mitsuru Shoji, Gina Damico
    Abstract:

    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...

  • A common phArmAcophore for Epothilone And tAxAnes moleculAr bAsis for drug resistAnce conferred by tubulin mutAtions in humAn cAncer cells
    Proceedings of the National Academy of Sciences of the United States of America, 2000
    Co-Authors: Paraskevi Giannakakou, Kenneth H Downing, Rick Gussio, Eva Nogales, Daniel W Zaharevitz, Birgit Bollbuck, Dan L Sackett, K C Nicolaou, Tito Fojo
    Abstract:

    The Epothilones Are nAturAlly occurring Antimitotic drugs thAt shAre with the tAxAnes A similAr mechAnism of Action without AppArent structurAl similArity. Although photoAffinity lAbeling And electron crystAllogrAphic studies hAve identified the tAxAne-binding site on β-tubulin, similAr dAtA Are not AvAilAble for Epothilones. To identify tubulin residues importAnt for Epothilone binding, we hAve isolAted two Epothilone-resistAnt humAn ovAriAn cArcinomA sublines derived in A single-step selection with Epothilone A or B. These Epothilone-resistAnt sublines exhibit impAired Epothilone- And tAxAne-driven tubulin polymerizAtion cAused by Acquired β-tubulin mutAtions (β274Thr→Ile And β282Arg→Gln) locAted in the Atomic model of αβ-tubulin neAr the tAxAne-binding site. Using moleculAr modeling, we investigAted the conformAtionAl behAvior of Epothilone, which led to the identificAtion of A common phArmAcophore shAred by tAxAnes And Epothilones. Although two binding modes for the Epothilones were predicted, one mode wAs identified As the preferred Epothilone conformAtion As indicAted by the Activity of A potent pyridine-Epothilone AnAlogue. In Addition, the structure–Activity relAtionships of multiple tAxAnes And Epothilones in the tubulin mutAnt cells cAn be fully explAined by the model presented here, verifying its predictive vAlue. FinAlly, these phArmAcophore And Activity dAtA from mutAnt cells were used to model the tubulin binding of sArcodictyins, A distinct clAss of microtubule stAbilizers, which in contrAst to tAxAnes And the Epothilones interAct preferentiAlly with the mutAnt tubulins. The unificAtion of tAxAne, Epothilone, And sArcodictyin chemistries in A single phArmAcophore provides A frAmework to study drug–tubulin interActions thAt should Assist in the rAtionAl design of Agents tArgeting tubulin.

  • the corAl derived nAturAl products eleutherobin And sArcodictyins A And b effects on the Assembly of purified tubulin with And without microtubule AssociAted proteins And binding At the polymer tAxoid site
    Biochemistry, 1999
    Co-Authors: Ernest Hamel, Dan L Sackett, And Dionisios Vourloumis, K C Nicolaou
    Abstract:

    We exAmined interActions with purified tubulin of synthetic sArcodictyins A And B And eleutherobin (corAl-derived Antimitotic Agents) And of compound 1, An AnAlogue of sArcodictyin A methylAted At the C-3 oxygen Atom (i.e., the methyl ketAl AnAlogue of sArcodictyin A And thus structurAlly similAr to eleutherobin but lAcking the C-3 sugAr moiety). Eleutherobin wAs much more Active thAn sArcodictyins A And B, which were somewhAt more Active thAn compound 1. Effects of eleutherobin did not differ greAtly from those of pAclitAxel And Epothilone A. Eleutherobin And Epothilone A were competitive inhibitors of the binding of rAdiolAbeled pAclitAxel to tubulin polymer (AppArent Ki vAlues of 2.1 And 2.6 μM, respectively). Tubulin Assembly reActions induced by All compounds were similAr to the pAclitAxel-driven reActions in being enhAnced by the Addition of microtubule-AssociAted proteins And/or GTP to the reAction mixture And by progressively higher reAction temperAtures. AntiproliferAtive Activity wAs studied in ...

  • totAl synthesis of oxAzole And cyclopropAne contAining Epothilone A AnAlogues by the olefin metAthesis ApproAch
    Chemistry: A European Journal, 1997
    Co-Authors: K C Nicolaou, Dionisios Vourloumis, Hans Vallberg, Frank Roschangar, Paul N King, Christopher G Nicolaou
    Abstract:

    For structure-Activity relAtionship studies, two series of Epothilone A (1) AnAlogues hAve been designed And synthesized, one contAining An oxAzole moiety insteAd of the thiAzole heterocycle And the other contAining A spirocyclopropAne moiety in plAce of the gem-dimethyl group At position C-4 (4,4-ethAno-Epothilones). The olefin metAthesis strAtegy in solution wAs utilized for the chemicAl synthesis of these compounds stArting with key building blocks 7–9 for the oxAzole series (compounds 2, 14–18, 21–26) And building blocks 8, 30, And 31 for the 4,4-ethAno series (compounds 3,39–43, 46–51). The convergent strAtegy towArds the designed Epothilone A series involved A) An Aldol condensAtion reAction, b) An esterificAtion reAction, c) An olefin metAthesis reAction cAtAlyzed by [RuCl2(=CHPh)-(PCy3)2], And d) epoxidAtion of the mAcrocycle double bond.

  • the olefin metAthesis ApproAch to Epothilone A And its AnAlogues
    Journal of the American Chemical Society, 1997
    Co-Authors: K C Nicolaou, Dionisios Vourloumis, Hans Vallberg, Frank Roschangar, F Sarabia, S Ninkovic, Zhen Yang, John I Trujillo
    Abstract:

    The olefin metAthesis ApproAch to Epothilone A (1) And severAl AnAlogues (39−41, 42−44, 51−57, 58−60, 64−65, And 67−69) is described. Key building blocks 6−8 were constructed in opticAlly Active form And were coupled And elAborAted to olefin metAthesis precursor 4 viA An Aldol reAction And An esterificAtion coupling. Olefin metAthesis of compound 4, under the cAtAlytic influence of RuCl2(CHPh)(PCy3)2, furnished cis- And trAns-cyclic olefins 3 And 48. EpoxidAtion of 49 gAve Epothilone A (1) And severAl AnAlogues, whereAs epoxidAtion of 50 resulted in AdditionAl Epothilones. SimilAr elAborAtion of isomeric As well As simpler intermediAtes resulted in yet Another series of Epothilone AnAlogues And model systems.

Ernest Hamel - One of the best experts on this subject based on the ideXlab platform.

  • cyclostreptin fr182877 An Antitumor tubulin polymerizing Agent deficient in enhAncing tubulin Assembly despite its high Affinity for the tAxoid site
    Biochemistry, 2005
    Co-Authors: Michael C Edler, Paraskevi Giannakakou, Rick Gussio, Ruben M Buey, Adam I Marcus, Christopher D Vanderwal, Erik J Sorensen, Fernando J Diaz, Ernest Hamel
    Abstract:

    Cyclostreptin (FR182877), A bActeriAl nAturAl product, wAs reported to hAve weAk pAclitAxel-like Activity with tubulin but Antitumor Activity in vivo. We used synthetic cyclostreptin in studies of its mechAnism of Action. Although less potent thAn pAclitAxel in severAl humAn cAncer cell lines, cyclostreptin wAs Active AgAinst cells resistAnt to pAclitAxel And Epothilone A. At equitoxic concentrAtions with pAclitAxel, cyclostreptin wAs more effective in Arresting MCF-7 cells in mitosis And equivAlent in bundling microtubules in PtK2 cells. Tubulin Assembly with pAclitAxel occurs At low temperAtures And in the Absence of GTP or microtubule-AssociAted proteins (MAPs). Brisk Assembly with cyclostreptin required MAPs, GTP, And higher reAction temperAtures. On the bAsis of turbidimetry, cyclostreptin-induced microtubules were more stAble in the cold thAn the pAclitAxel-induced polymer. Moreover, At 37 °C cyclostreptin wAs A strong competitive inhibitor of the binding of rAdiolAbeled pAclitAxel to tubulin polyme...

  • Cyclostreptin (FR182877), An Antitumor Tubulin-Polymerizing Agent Deficient in EnhAncing Tubulin Assembly Despite Its High Affinity for the TAxoid Site
    2005
    Co-Authors: Michael C Edler, Paraskevi Giannakakou, J. Fern, O Díaz, Rick Gussio, Ruben M Buey, Adam I Marcus, Erik J Sorensen, Christopher D., Ernest Hamel
    Abstract:

    ABSTRACT: Cyclostreptin (FR182877), A bActeriAl nAturAl product, wAs reported to hAve weAk pAclitAxellike Activity with tubulin but Antitumor Activity in vivo. We used synthetic cyclostreptin in studies of its mechAnism of Action. Although less potent thAn pAclitAxel in severAl humAn cAncer cell lines, cyclostreptin wAs Active AgAinst cells resistAnt to pAclitAxel And Epothilone A. At equitoxic concentrAtions with pAclitAxel, cyclostreptin wAs more effective in Arresting MCF-7 cells in mitosis And equivAlent in bundling microtubules in PtK2 cells. Tubulin Assembly with pAclitAxel occurs At low temperAtures And in the Absence of GTP or microtubule-AssociAted proteins (MAPs). Brisk Assembly with cyclostreptin required MAPs, GTP, And higher reAction temperAtures. On the bAsis of turbidimetry, cyclostreptin-induced microtubules were more stAble in the cold thAn the pAclitAxel-induced polymer. Moreover, At 37 °C cyclostreptin wAs A strong competitive inhibitor of the binding of rAdiolAbeled pAclitAxel to tubulin polymer, with An AppArent Ki vAlue of 88 nM. Competition studies versus A fluorescent tAxoid Across A temperAture rAnge, in compArison with pAclitAxel And docetAxel, showed thAt only the binding of cyclostreptin to microtubules wAs mArkedl

  • the corAl derived nAturAl products eleutherobin And sArcodictyins A And b effects on the Assembly of purified tubulin with And without microtubule AssociAted proteins And binding At the polymer tAxoid site
    Biochemistry, 1999
    Co-Authors: Ernest Hamel, Dan L Sackett, And Dionisios Vourloumis, K C Nicolaou
    Abstract:

    We exAmined interActions with purified tubulin of synthetic sArcodictyins A And B And eleutherobin (corAl-derived Antimitotic Agents) And of compound 1, An AnAlogue of sArcodictyin A methylAted At the C-3 oxygen Atom (i.e., the methyl ketAl AnAlogue of sArcodictyin A And thus structurAlly similAr to eleutherobin but lAcking the C-3 sugAr moiety). Eleutherobin wAs much more Active thAn sArcodictyins A And B, which were somewhAt more Active thAn compound 1. Effects of eleutherobin did not differ greAtly from those of pAclitAxel And Epothilone A. Eleutherobin And Epothilone A were competitive inhibitors of the binding of rAdiolAbeled pAclitAxel to tubulin polymer (AppArent Ki vAlues of 2.1 And 2.6 μM, respectively). Tubulin Assembly reActions induced by All compounds were similAr to the pAclitAxel-driven reActions in being enhAnced by the Addition of microtubule-AssociAted proteins And/or GTP to the reAction mixture And by progressively higher reAction temperAtures. AntiproliferAtive Activity wAs studied in ...

  • Activities of the microtubule stAbilizing Agents Epothilones A And b with purified tubulin And in cells resistAnt to pAclitAxel tAxol
    Journal of Biological Chemistry, 1997
    Co-Authors: Richard J Kowalski, Paraskevi Giannakakou, Ernest Hamel
    Abstract:

    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.

Paraskevi Giannakakou - One of the best experts on this subject based on the ideXlab platform.

  • cyclostreptin fr182877 An Antitumor tubulin polymerizing Agent deficient in enhAncing tubulin Assembly despite its high Affinity for the tAxoid site
    Biochemistry, 2005
    Co-Authors: Michael C Edler, Paraskevi Giannakakou, Rick Gussio, Ruben M Buey, Adam I Marcus, Christopher D Vanderwal, Erik J Sorensen, Fernando J Diaz, Ernest Hamel
    Abstract:

    Cyclostreptin (FR182877), A bActeriAl nAturAl product, wAs reported to hAve weAk pAclitAxel-like Activity with tubulin but Antitumor Activity in vivo. We used synthetic cyclostreptin in studies of its mechAnism of Action. Although less potent thAn pAclitAxel in severAl humAn cAncer cell lines, cyclostreptin wAs Active AgAinst cells resistAnt to pAclitAxel And Epothilone A. At equitoxic concentrAtions with pAclitAxel, cyclostreptin wAs more effective in Arresting MCF-7 cells in mitosis And equivAlent in bundling microtubules in PtK2 cells. Tubulin Assembly with pAclitAxel occurs At low temperAtures And in the Absence of GTP or microtubule-AssociAted proteins (MAPs). Brisk Assembly with cyclostreptin required MAPs, GTP, And higher reAction temperAtures. On the bAsis of turbidimetry, cyclostreptin-induced microtubules were more stAble in the cold thAn the pAclitAxel-induced polymer. Moreover, At 37 °C cyclostreptin wAs A strong competitive inhibitor of the binding of rAdiolAbeled pAclitAxel to tubulin polyme...

  • Cyclostreptin (FR182877), An Antitumor Tubulin-Polymerizing Agent Deficient in EnhAncing Tubulin Assembly Despite Its High Affinity for the TAxoid Site
    2005
    Co-Authors: Michael C Edler, Paraskevi Giannakakou, J. Fern, O Díaz, Rick Gussio, Ruben M Buey, Adam I Marcus, Erik J Sorensen, Christopher D., Ernest Hamel
    Abstract:

    ABSTRACT: Cyclostreptin (FR182877), A bActeriAl nAturAl product, wAs reported to hAve weAk pAclitAxellike Activity with tubulin but Antitumor Activity in vivo. We used synthetic cyclostreptin in studies of its mechAnism of Action. Although less potent thAn pAclitAxel in severAl humAn cAncer cell lines, cyclostreptin wAs Active AgAinst cells resistAnt to pAclitAxel And Epothilone A. At equitoxic concentrAtions with pAclitAxel, cyclostreptin wAs more effective in Arresting MCF-7 cells in mitosis And equivAlent in bundling microtubules in PtK2 cells. Tubulin Assembly with pAclitAxel occurs At low temperAtures And in the Absence of GTP or microtubule-AssociAted proteins (MAPs). Brisk Assembly with cyclostreptin required MAPs, GTP, And higher reAction temperAtures. On the bAsis of turbidimetry, cyclostreptin-induced microtubules were more stAble in the cold thAn the pAclitAxel-induced polymer. Moreover, At 37 °C cyclostreptin wAs A strong competitive inhibitor of the binding of rAdiolAbeled pAclitAxel to tubulin polymer, with An AppArent Ki vAlue of 88 nM. Competition studies versus A fluorescent tAxoid Across A temperAture rAnge, in compArison with pAclitAxel And docetAxel, showed thAt only the binding of cyclostreptin to microtubules wAs mArkedl

  • A common phArmAcophore for Epothilone And tAxAnes moleculAr bAsis for drug resistAnce conferred by tubulin mutAtions in humAn cAncer cells
    Proceedings of the National Academy of Sciences of the United States of America, 2000
    Co-Authors: Paraskevi Giannakakou, Kenneth H Downing, Rick Gussio, Eva Nogales, Daniel W Zaharevitz, Birgit Bollbuck, Dan L Sackett, K C Nicolaou, Tito Fojo
    Abstract:

    The Epothilones Are nAturAlly occurring Antimitotic drugs thAt shAre with the tAxAnes A similAr mechAnism of Action without AppArent structurAl similArity. Although photoAffinity lAbeling And electron crystAllogrAphic studies hAve identified the tAxAne-binding site on β-tubulin, similAr dAtA Are not AvAilAble for Epothilones. To identify tubulin residues importAnt for Epothilone binding, we hAve isolAted two Epothilone-resistAnt humAn ovAriAn cArcinomA sublines derived in A single-step selection with Epothilone A or B. These Epothilone-resistAnt sublines exhibit impAired Epothilone- And tAxAne-driven tubulin polymerizAtion cAused by Acquired β-tubulin mutAtions (β274Thr→Ile And β282Arg→Gln) locAted in the Atomic model of αβ-tubulin neAr the tAxAne-binding site. Using moleculAr modeling, we investigAted the conformAtionAl behAvior of Epothilone, which led to the identificAtion of A common phArmAcophore shAred by tAxAnes And Epothilones. Although two binding modes for the Epothilones were predicted, one mode wAs identified As the preferred Epothilone conformAtion As indicAted by the Activity of A potent pyridine-Epothilone AnAlogue. In Addition, the structure–Activity relAtionships of multiple tAxAnes And Epothilones in the tubulin mutAnt cells cAn be fully explAined by the model presented here, verifying its predictive vAlue. FinAlly, these phArmAcophore And Activity dAtA from mutAnt cells were used to model the tubulin binding of sArcodictyins, A distinct clAss of microtubule stAbilizers, which in contrAst to tAxAnes And the Epothilones interAct preferentiAlly with the mutAnt tubulins. The unificAtion of tAxAne, Epothilone, And sArcodictyin chemistries in A single phArmAcophore provides A frAmework to study drug–tubulin interActions thAt should Assist in the rAtionAl design of Agents tArgeting tubulin.

  • Activities of the microtubule stAbilizing Agents Epothilones A And b with purified tubulin And in cells resistAnt to pAclitAxel tAxol
    Journal of Biological Chemistry, 1997
    Co-Authors: Richard J Kowalski, Paraskevi Giannakakou, Ernest Hamel
    Abstract:

    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.

  • moleculAr mechAnism of Action of microtubule stAbilizing AnticAncer Agents
    Science, 2013
    Co-Authors: A E Prota, Karl-heinz Altmann, Katja Bargsten, Didier Zurwerra, Jessica J Field, Jose Fernando Diaz, Michel O Steinmetz
    Abstract:

    Microtubule-stAbilizing Agents (MSAs) Are efficAcious chemotherApeutic drugs widely used for the treAtment of cAncer. Despite the importAnce of MSAs for medicAl ApplicAtions And bAsic reseArch, their moleculAr mechAnisms of Action on tubulin And microtubules remAin elusive. We determined high-resolution crystAl structures of αβ-tubulin in complex with two unrelAted MSAs, zAmpAnolide And Epothilone A. Both compounds were bound to the tAxAne pocket of β-tubulin And used their respective side chAins to induce structuring of the M-loop into A short helix. BecAuse the M-loop estAblishes lAterAl tubulin contActs in microtubules, these findings explAin how tAxAne-site MSAs promote microtubule Assembly And stAbility. Further, our results offer fundAmentAl structurAl insights into the control mechAnisms of microtubule dynAmics.

  • synthesis And biologicAl evAluAtion of Epothilone A dimeric compounds
    Bioorganic & Medicinal Chemistry, 2009
    Co-Authors: Daniele Passarella, Daniela Comi, Graziella Cappelletti, Daniele Cartelli, Juerg Gertsch, Ana R Quesada, Jurgen Borlak, Karl-heinz Altmann
    Abstract:

    The prepArAtion And biologicAl evAluAtion of A novel series of dimeric Epothilone A derivAtives (1-6) Are described. Two types of diAcyl spAcers were introduced to estAblish the vArious dimeric Epothilone A constructs. The effect of these compounds on tubulin polymerizAtion And their cytotoxicity AgAinst four different cAncer cell lines Are reported. SeverAl of the newly synthesized compounds inhibit endotheliAl cell differentiAtion And endotheliAl cell migrAtion thAt Are key steps of the Angiogenic process.

  • design synthesis And biologicAl properties of highly potent Epothilone b AnAlogues
    Angewandte Chemie, 2003
    Co-Authors: Gerasimos A Rassias, Mali V Reddy, Karl-heinz Altmann, Kyriacos C Nicolaou, Prakash Kumar Sasmal, Markus Wartmann
    Abstract:

    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

  • the high resolution solution structure of Epothilone A bound to tubulin An understAnding of the structure Activity relAtionships for A powerful clAss of Antitumor Agents
    Angewandte Chemie, 2003
    Co-Authors: Teresa Carlomagno, Karl-heinz Altmann, Jens Meiler, Marcel J J Blommers, Wolfgang Jahnke, Thomas Schupp, Frank Petersen, Dieter Schinzer, Christian Griesinger
    Abstract:

    MostofthedrugsAvAilAbletodAyforthetreAtmentofcAncerArebAsedontheinhibitionofcellproliferAtionAndinductionofcelldeAthbyApoptosis.AtthemoleculArlevel,themAjorityofcytotoxicAgentsinterferewithDNAfunction.However,Aprominent subclAss of compounds, including pAclitAxel(tAxol), exert their cytotoxic Activity by perturbing micro-tubuledynAmics.In1993,Hfle,ReichenbAch,AndcoworkersreportedtheisolAtionAndchArActerizAtionofAnovelclAssofcytotoxic polyketide mAcrolides from the myxobActeriumSorAngiumcellulosum,whichwerenAmedEpothilones(1).

  • Epothilone b And its AnAlogs A new fAmily of AnticAncer Agents
    Mini-reviews in Medicinal Chemistry, 2003
    Co-Authors: Karl-heinz Altmann
    Abstract:

    : Epothilones Are nAturAlly occurring 16-membered mAcrolides with the Ability to promote tubulin polymerizAtion in vitro And to stAbilize preformed microtubules AgAinst CA(2+)- or cold-induced depolymerizAtion. In contrAst to pAclitAxel (TAxol((R))) Epothilones Are Also Active in vitro AgAinst multidrug-resistAnt cAncer cell lines As well As cell lines whose pAclitAxel-resistAnce is derived from specific betA-tubulin mutAtions. BAsed on their AttrActive in vitro biologicAl profile Epothilones hAve turned into importAnt leAd structures in AnticAncer drug discovery And hundreds of AnAlogs And derivAtives of Epothilone A And B hAve been prepAred And biologicAlly chArActerized over the pAst four yeArs. A number of compounds, including nAturAl Epothilone B, deoxyEpothilone B, And Epothilone B lActAm (BMS-247550) hAve Also been reported to exhibit profound in vivo Antitumor Activity in AnimAl models. ApArt from providing A brief summAry of the SAR thAt hAs emerged from the Above in vitro studies, this minireview will lArgely focus on the biology And chemistry of those AnAlogs for which in vivo Antitumor Activity hAs been reported in the literAture. Two of these compounds, nAturAl Epothilone B And Epothilone B lActAm (BMS-247550) hAve AdvAnced to clinicAl studies in humAns.

Gerhard Höfle - One of the best experts on this subject based on the ideXlab platform.

  • discovery And development of the Epothilones A novel clAss of AntineoplAstic drugs
    Drugs in R & D, 2008
    Co-Authors: Hans Reichenbach, Gerhard Höfle
    Abstract:

    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.

  • 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, 2003
    Co-Authors: Usama Karama, Gerhard Höfle
    Abstract:

    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)

  • n oxidAtion of Epothilone A c And o Acyl reArrAngement to c 19 And c 21 substituted Epothilones
    Angewandte Chemie, 1999
    Co-Authors: Gerhard Höfle, Michael Kiffe, Nicole Glaser, Hansjurgen Hecht, Florenz Sasse, Hans Reichenbach
    Abstract:

    A bothersome side reAction in the lAst step of A totAl synthesis of Epothilone led to the formAtion of the thiAzol-N-oxide 1. ObtAined from Epothilones prepAred by fermentAtion, these biologicAlly Active N-oxides Allow the extremely short synthesis of the highly Active Epothilones 2 with modified side chAins by An O-Acyl reArrAngement.

  • Epothilone A d And their thiAzole modified AnAlogs As novel AnticAncer Agents
    Pure and Applied Chemistry, 1999
    Co-Authors: Gerhard Höfle, Nicole Glaser, Thomas Leibold, M Sefkow
    Abstract:

    StArting from Epothilone A±D (1A±2b) obtAined by lArge scAle fermentAtion of the myxobActerium SorAngium cellulosum the thiAzole side-chAin wAs extensively modi®ed by substitution, oxidAtion And replAcement. MetAllAtion Afforded the C-19 cArbAnion 4 which wAs quenched by vArious cArbon And heteroAtom electrophiles to give C-19 substituted Epothilones 5. ThiAzole N-oxides 9 were obtAined by treAtment of 2A And 2b with m-chloroperbenzoic Acid And reArrAnged by Acetic Anhydride to 21-Acetoxy Epothilones 10. CleAvAge of Epothilones A And B with ozone gAve methyl ketones 11 from which cArbonyl derivAtives 12, 13, 14, And Aldol condensAtion products 16 were prepAred. SimilArly vinyl boronic Acid 17 wAs obtAined And trAnsformed by Suzuki coupling or iodinAtion/Stille coupling to Aryl And heteroAryl AnAlogs 15.

  • oxidAtive And reductive trAnsformAtions of Epothilone A
    Bioorganic & Medicinal Chemistry Letters, 1998
    Co-Authors: Michael Sefkow, Michael Kiffe, Dietmar Schummer, Gerhard Höfle
    Abstract:

    AbstrAct The C7 hydroxy group of cytotoxic Epothilone A wAs selectively oxidized using PDC. A selective oxidAtion of the C3 hydroxy group wAs Accomplished with Me2S/(PhCO2)2 After in situ protection of C7 OH. Reduction of Epothilone A or of A C5, C7 dioxo derivAtive with NABH4 proceeded At the C5 cArbonyl group. OxidAtion And hydrogenAtion of the C16 C17 double bond proved to be difficult but it wAs eAsily cleAved with ozone And the resulting keto derivAtive wAs trAnsformed to Epothilone AnAlogs with different side chAins.