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Norbert Sewald - One of the best experts on this subject based on the ideXlab platform.
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Conjugates of Modified Cryptophycins and RGD-Peptides Enter Target Cells by Endocytosis
2016Co-Authors: Markus Nahrwold, Christine Weiß, Tobias Bogner, Felix Mertink, Jens Conradi, Benedikt Sammet, Ralf Palmisano, Soledad Royo Gracia, Thomas Preuße, Norbert SewaldAbstract:Tumor targeting anticancer drug conjugates that contain a tumor recognition motif (homing device) are of high current relevance. Cryptophycins, naturally occurring cytotoxic cyclo-depsipeptides, have been modified by total synthesis to provide analogues suitable for conjugation to peptide-based homing devices. An array of functionalized β2-amino acids was synthesized and incorporated into Cryptophycins. All analogues proved to be highly active in the cytotoxicity assay using the human cervix carcinoma cell line KB-3-1 and its multidrug-resistant subclone KB-V1. Conformational analysis of Cryptophycin-52 and two synthetic analogues was performed by NMR and MD methods to obtain information on the influence of the unit C configuration on the overall conformation. An azide-functionalized Cryptophycin was connected by CuAAC to an alkyne-containing fluorescently labeled cyclic RGD-peptide as the homing device for internalization studies. Confocal fluorescence microscopy proved integrin-mediated internalization by endocytosis and final lysosomal localization of the Cryptophycin prodrug
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"Clicktophycin-52": a bioactive Cryptophycin-52 triazole analogue.
Organic letters, 2010Co-Authors: Markus Nahrwold, Tobias Bogner, Stefan Eissler, Spart Verma, Norbert SewaldAbstract:An endocyclic trans-amide linkage within the macrocyclic antitumor agent Cryptophycin-52 was replaced by a 1,4-disubstituted 1H-1,2,3-triazole ring. Macrocyclisation of the triazole analogue was accomplished by macrolactamization as well as by Cu(I)-mediated “click”-cyclization. Compared to Cryptophycin-52, in vitro cytotoxicity of “clicktophycin-52” against the multidrug resistant human cancer cell line KB-V1 is only slightly reduced.
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efficient synthesis of Cryptophycin 52 and novel para alkoxymethyl unit a analogues
Chemistry: A European Journal, 2009Co-Authors: Stefan Eisler, Tobias Bogner, Markus Nahrwold, Norbert SewaldAbstract:Cryptophycins are a family of highly cytotoxic, cyclic depsipeptides. They display antitumour activity that is largely maintained for multidrug-resistant tumour cells. Cryptophycins are composed of four building blocks (units A-D) that correspond to the respective amino and hydroxy acids. A new synthetic route to unit A allows the selective generation of all four stereogenic centres in a short, efficient and reliable synthesis and contributes to an easier and faster synthesis of Cryptophycins. The first two stereogenic centres are introduced by a catalytic asymmetric dihydroxylation, whereas the remaining two stereogenic centres are introduced with substrate control of diastereoselectivity. The stereogenic diol function also serves as the epoxide precursor. The approach was used to synthesise the native unit A building block as well as three para-alkoxymethyl analogues from which Cryptophycin-52 and three analogous Cryptophycins were prepared. Macro-cyclisation of the seco-depsipeptides was based on ring-closing metathesis.
Markus Nahrwold - One of the best experts on this subject based on the ideXlab platform.
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Conjugates of Modified Cryptophycins and RGD-Peptides Enter Target Cells by Endocytosis
2016Co-Authors: Markus Nahrwold, Christine Weiß, Tobias Bogner, Felix Mertink, Jens Conradi, Benedikt Sammet, Ralf Palmisano, Soledad Royo Gracia, Thomas Preuße, Norbert SewaldAbstract:Tumor targeting anticancer drug conjugates that contain a tumor recognition motif (homing device) are of high current relevance. Cryptophycins, naturally occurring cytotoxic cyclo-depsipeptides, have been modified by total synthesis to provide analogues suitable for conjugation to peptide-based homing devices. An array of functionalized β2-amino acids was synthesized and incorporated into Cryptophycins. All analogues proved to be highly active in the cytotoxicity assay using the human cervix carcinoma cell line KB-3-1 and its multidrug-resistant subclone KB-V1. Conformational analysis of Cryptophycin-52 and two synthetic analogues was performed by NMR and MD methods to obtain information on the influence of the unit C configuration on the overall conformation. An azide-functionalized Cryptophycin was connected by CuAAC to an alkyne-containing fluorescently labeled cyclic RGD-peptide as the homing device for internalization studies. Confocal fluorescence microscopy proved integrin-mediated internalization by endocytosis and final lysosomal localization of the Cryptophycin prodrug
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"Clicktophycin-52": a bioactive Cryptophycin-52 triazole analogue.
Organic letters, 2010Co-Authors: Markus Nahrwold, Tobias Bogner, Stefan Eissler, Spart Verma, Norbert SewaldAbstract:An endocyclic trans-amide linkage within the macrocyclic antitumor agent Cryptophycin-52 was replaced by a 1,4-disubstituted 1H-1,2,3-triazole ring. Macrocyclisation of the triazole analogue was accomplished by macrolactamization as well as by Cu(I)-mediated “click”-cyclization. Compared to Cryptophycin-52, in vitro cytotoxicity of “clicktophycin-52” against the multidrug resistant human cancer cell line KB-V1 is only slightly reduced.
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efficient synthesis of Cryptophycin 52 and novel para alkoxymethyl unit a analogues
Chemistry: A European Journal, 2009Co-Authors: Stefan Eisler, Tobias Bogner, Markus Nahrwold, Norbert SewaldAbstract:Cryptophycins are a family of highly cytotoxic, cyclic depsipeptides. They display antitumour activity that is largely maintained for multidrug-resistant tumour cells. Cryptophycins are composed of four building blocks (units A-D) that correspond to the respective amino and hydroxy acids. A new synthetic route to unit A allows the selective generation of all four stereogenic centres in a short, efficient and reliable synthesis and contributes to an easier and faster synthesis of Cryptophycins. The first two stereogenic centres are introduced by a catalytic asymmetric dihydroxylation, whereas the remaining two stereogenic centres are introduced with substrate control of diastereoselectivity. The stereogenic diol function also serves as the epoxide precursor. The approach was used to synthesise the native unit A building block as well as three para-alkoxymethyl analogues from which Cryptophycin-52 and three analogous Cryptophycins were prepared. Macro-cyclisation of the seco-depsipeptides was based on ring-closing metathesis.
Sewald Norbert - One of the best experts on this subject based on the ideXlab platform.
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Cryptophycins: cytotoxic cyclodepsipeptides with potential for tumor targeting
'Wiley', 2017Co-Authors: Weiss Christine, Figueras Agustí Eduard, Borbély, Adina Noémi, Sewald NorbertAbstract:Weiss C, Figueras Agustí E, Borbély AN, Sewald N. Cryptophycins: cytotoxic cyclodepsipeptides with potential for tumor targeting. Journal of Peptide Science. 2017;23(7-8):514-531.Cryptophycins are a class of 16-membered highly cytotoxic macrocyclic depsipeptides isolated from cyanobacteria. The biological activity is based on their ability to interact with tubulin. They interfere with microtubule dynamics and prevent microtubules from forming correct mitotic spindles, which causes cell-cycle arrest and apoptosis. Their strong antiproliferative activities with 100-fold to 1000-fold potency compared with those of paclitaxel and vinblastine have been observed. Cryptophycins are highly promising drug candidates, as their biological activity is not negatively affected by P-glycoprotein, a drug efflux system commonly found in multidrug-resistant cancer cell lines and solid tumors. Cryptophycin-52 had been investigated in phase II clinical trials but failed because of its high neurotoxicity. Recently, Cryptophycin conjugates with peptides and antibodies have been developed for targeted delivery in tumor therapy. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd
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Conjugates of modified Cryptophycins and RGD-peptides enter target cells by endocytosis
'American Chemical Society (ACS)', 2013Co-Authors: Nahrwold Markus, Sammet Benedikt, Bogner Tobias, Weiss Christine, Mertink Felix, Conradi Jens, Palmisano Ralf, Royo Gracia Soledad, Preuße Thomas, Sewald NorbertAbstract:Nahrwold M, Weiß C, Bogner T, et al. Conjugates of modified Cryptophycins and RGD-peptides enter target cells by endocytosis. Journal of Medicinal Chemistry. 2013;56(5):1853-1864.Tumor targeting anticancer drug conjugates that contain a tumor recognition motif (homing device) are of high current relevance. Cryptophycins, naturally occurring cytotoxic cyclo-depsipeptides, have been modified by total synthesis to provide analogues suitable for conjugation to peptide-based homing devices. An array of functionalized β(2)-amino acids was synthesized and incorporated into Cryptophycins. All analogues proved to be highly active in the cytotoxicity assay using the human cervix carcinoma cell line KB-3-1 and its multidrug-resistant subclone KB-V1. Conformational analysis of Cryptophycin-52 and two synthetic analogues was performed by NMR and MD methods to obtain information on the influence of the unit C configuration on the overall conformation. An azide-functionalized Cryptophycin was connected by CuAAC to an alkyne-containing fluorescently labeled cyclic RGD-peptide as the homing device for internalization studies. Confocal fluorescence microscopy proved integrin-mediated internalization by endocytosis and final lysosomal localization of the Cryptophycin prodrug
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Approaches for the Synthesis of Functionalized Cryptophycins
'American Chemical Society (ACS)', 2010Co-Authors: Sammet Benedikt, Bogner Tobias, Nahrwold Markus, Weiss Christine, Sewald NorbertAbstract:Sammet B, Bogner T, Nahrwold M, Weiss C, Sewald N. Approaches for the Synthesis of Functionalized Cryptophycins. Journal of Organic Chemistry. 2010;75(20):6953-6960.The first syntheses of bioactive Cryptophycins functionalized at unit ID were accomplished ina one-pot Staudinger reduction/cyclization step An a/ado precursor for the lower part of the backbone was introduced to minimize protective group chemistry and enable a very convenient synthesis of Cryptophycin-52 and unit D eryptophycin analogues containing an ester or a free carboxylic acid for bioconjugations Both new Cryptophycin derivatives show high biological activity in cytotoxicity assay
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"Clicktophycin-52": A Bioactive Cryptophycin-52 Triazole Analogue
'American Chemical Society (ACS)', 2010Co-Authors: Nahrwold Markus, Bogner Tobias, Eißler Stefan, Verma Spart, Sewald NorbertAbstract:Nahrwold M, Bogner T, Eissler S, Verma S, Sewald N. "Clicktophycin-52": A Bioactive Cryptophycin-52 Triazole Analogue. Organic Letters. 2010;12(5):1064-1067.An endocyclic trans-amide linkage within the macrocyclic antitumor agent Cryptophycin-52 was replaced by a 1,4-disubstituted 1H-1,2,3-triazole ring. Macrocyclisation of the triazole analogue was accomplished by macrolactamization as well as by Cu(I)-mediated "click"-cyclization. Compared to Cryptophycin-52, in vitro cytotoxicity of "clicktophycin-52" against the multidrug resistant human cancer cell line KB-V1 is only slightly reduced
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Efficient Synthesis of Cryptophycin-52 and Novel para-Alkoxymethyl Unit A Analogues
'Wiley', 2009Co-Authors: Eißler Stefan, Nahrwold Markus, Bogner Tobias, Sewald NorbertAbstract:Eissler S, Bogner T, Nahrwold M, Sewald N. Efficient Synthesis of Cryptophycin-52 and Novel para-Alkoxymethyl Unit A Analogues. Chemistry - A European Journal. 2009;15(42):11273-11287.Cryptophycins are a family of highly cytotoxic, cyclic depsipeptides. They display antitumour activity that is largely maintained for multidrug-resistant tumour cells. Cryptophycins are composed of four building blocks (units A-D) that correspond to the respective amino and hydroxy acids. A new synthetic route to unit A allows the selective generation of all four stereogenic centres in a short, efficient and reliable synthesis and contributes to an easier and faster synthesis of Cryptophycins. The first two stereogenic centres are introduced by a catalytic asymmetric dihydroxylation, whereas the remaining two stereogenic centres are introduced with substrate control of diastercoselectivity. The stereogenic diol function also serves as the epoxide precursor. The approach was used to synthesise the native unit A building block as well as three para-alkoxymethyl analogues from which Cryptophycin-52 and three analogous Cryptophycins were prepared. Macrocyclisation of the seco-depsipeptides was based on ring-closing metathesis
Leslie Wilson - One of the best experts on this subject based on the ideXlab platform.
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Interaction of the Antitumor Compound Cryptophycin-52 with Tubulin†
Biochemistry, 2000Co-Authors: Dulal Panda, Chuan Shih, Mary Ann Jordan, Vidya Ananthnarayan, Gary Larson, Leslie WilsonAbstract:Cryptophycin-52 (LY355703) is currently undergoing clinical evaluation for cancer chemotherapy. It is a potent suppresser of microtubule dynamics in vitro, and low picomolar concentrations appear to inhibit cancer cell proliferation at mitosis by stabilizing spindle microtubules. In the present study, using [3H]Cryptophycin-52, we found that the compound bound to tubulin at a single high-affinity site [apparent Ka (3.6 ± 1) × 106 L/mol, 34 °C]. The binding of Cryptophycin-52 to tubulin was rapid, not appreciably temperature-dependent, and very poorly reversible. However, we could remove [3H]Cryptophycin-52 from [3H]Cryptophycin-52−tubulin complex by denaturing the complex with either urea treatment or boiling. These data suggest that the binding of Cryptophycin-52 to tubulin is not covalent. A van't Hoff plot of the binding data indicated that the binding of Cryptophycin-52 to tubulin is primarily entropy-driven with a minimum enthalpy contribution. In addition, Cryptophycin-52 perturbed the far-ultraviol...
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In vitro pharmacology of Cryptophycin 52 (LY355703) in human tumor cell lines
Cancer Chemotherapy and Pharmacology, 1999Co-Authors: Margaret M. Wagner, Chuan Shih, Mary Ann Jordan, Leslie Wilson, Donald C. Paul, D. C. WilliamsAbstract:Purpose : Cryptophycin 52 (LY355703) is a new member of the Cryptophycin family of antitumor agents that is currently undergoing clinical evaluation for cancer chemotherapy. The mechanism of action of the Cryptophycin class of compounds is associated with an action on microtubules. This report details the pharmacological profile of this new clinical compound in a panel of human tumor cell lines. Methods : Antiproliferative effects of Cryptophycin 52 were measured indirectly by detection of the metabolic reduction of alamarBlue^®. Cytoxicity was assessed by enzymatic dye activation (calcein AM) combined with dye exclusion (ethidium homodimer) and by clonogenicity assay. Cell cycle effects were evaluated using flow cytometry and fluorescence microscopy. Results : Both antiproliferative and cytotoxic effects of Cryptophycin 52 were concentration- and time-dependent. IC_50 values for antiproliferative activity in both solid and hematologic tumor cell lines were in the low picomolar range, and without exception, were significantly below values for the antimitotic agents paclitaxel and vinblastine. Flow cytometry and microscopic examination of tumor cells treated with Cryptophycin 52 indicated that they accumulated in the mitotic phase of the cell cycle. Cryptophycin 52 was tested for its sensitivity to multidrug-resistance in several paired cell lines in which a sensitive parental line was matched with a multidrug-resistant derivative line. The resistant lines have been shown to over express Pgp and/or MRP multidrug-resistance transport factors. Compared to other antimitotic agents (paclitaxel, vinblastine, vincristine), the potency of Cryptophycin 52 was shown to be minimally affected in multidrug-resistant cells compared to their sensitive parental lines. Conclusion : Cryptophycin 52 has potent antimitotic, antiproliferative and cytotoxic activity in in vitro human tumor cell models. It is significantly more potent and less sensitive to multidrug resistance mechanisms than other antimitotic antitumor agents currently used in cancer therapy. These characteristics may translate into therapeutic advantages for the clinical use of Cryptophycin 52 in cancer chemotherapy.
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Antiproliferative mechanism of action of Cryptophycin-52: Kinetic stabilization of microtubule dynamics by high-affinity binding to microtubule ends
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Dulal Panda, Keith F. Deluca, Daniel C. Williams, Mary Ann Jordan, Leslie WilsonAbstract:Cryptophycin-52 (LY355703) is a new synthetic member of the Cryptophycin family of antimitotic antitumor agents that is currently undergoing clinical evaluation. At high concentrations (≥10 times the IC50), Cryptophycin-52 blocked HeLa cell proliferation at mitosis by depolymerizing spindle microtubules and disrupting chromosome organization. However, low concentrations of Cryptophycin-52 inhibited cell proliferation at mitosis (IC50 = 11 pM) without significantly altering spindle microtubule mass or organization. Cryptophycin-52 appears to be the most potent suppressor of microtubule dynamics found thus far. It suppressed the dynamic instability behavior of individual microtubules in vitro (IC50 = 20 nM), reducing the rate and extent of shortening and growing without significantly reducing polymer mass or mean microtubule length. Using [3H]Cryptophycin-52, we found that the compound bound to microtubule ends in vitro with high affinity (Kd, 47 nM, maximum of ≈19.5 Cryptophycin-52 molecules per microtubule). By analyzing the effects of Cryptophycin-52 on dynamics in relation to its binding to microtubules, we determined that ≈5–6 molecules of Cryptophycin-52 bound to a microtubule were sufficient to decrease dynamicity by 50%. Cryptophycin-52 became concentrated in cells 730-fold, and the resulting intracellular Cryptophycin-52 concentration was similar to that required to stabilize microtubule dynamics in vitro. The data suggest that Cryptophycin-52 potently perturbs kinetic events at microtubule ends that are required for microtubule function during mitosis and that it acts by forming a reversible Cryptophycin-52-tubulin stabilizing cap at microtubule ends.
Tobias Bogner - One of the best experts on this subject based on the ideXlab platform.
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Conjugates of Modified Cryptophycins and RGD-Peptides Enter Target Cells by Endocytosis
2016Co-Authors: Markus Nahrwold, Christine Weiß, Tobias Bogner, Felix Mertink, Jens Conradi, Benedikt Sammet, Ralf Palmisano, Soledad Royo Gracia, Thomas Preuße, Norbert SewaldAbstract:Tumor targeting anticancer drug conjugates that contain a tumor recognition motif (homing device) are of high current relevance. Cryptophycins, naturally occurring cytotoxic cyclo-depsipeptides, have been modified by total synthesis to provide analogues suitable for conjugation to peptide-based homing devices. An array of functionalized β2-amino acids was synthesized and incorporated into Cryptophycins. All analogues proved to be highly active in the cytotoxicity assay using the human cervix carcinoma cell line KB-3-1 and its multidrug-resistant subclone KB-V1. Conformational analysis of Cryptophycin-52 and two synthetic analogues was performed by NMR and MD methods to obtain information on the influence of the unit C configuration on the overall conformation. An azide-functionalized Cryptophycin was connected by CuAAC to an alkyne-containing fluorescently labeled cyclic RGD-peptide as the homing device for internalization studies. Confocal fluorescence microscopy proved integrin-mediated internalization by endocytosis and final lysosomal localization of the Cryptophycin prodrug
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"Clicktophycin-52": a bioactive Cryptophycin-52 triazole analogue.
Organic letters, 2010Co-Authors: Markus Nahrwold, Tobias Bogner, Stefan Eissler, Spart Verma, Norbert SewaldAbstract:An endocyclic trans-amide linkage within the macrocyclic antitumor agent Cryptophycin-52 was replaced by a 1,4-disubstituted 1H-1,2,3-triazole ring. Macrocyclisation of the triazole analogue was accomplished by macrolactamization as well as by Cu(I)-mediated “click”-cyclization. Compared to Cryptophycin-52, in vitro cytotoxicity of “clicktophycin-52” against the multidrug resistant human cancer cell line KB-V1 is only slightly reduced.
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efficient synthesis of Cryptophycin 52 and novel para alkoxymethyl unit a analogues
Chemistry: A European Journal, 2009Co-Authors: Stefan Eisler, Tobias Bogner, Markus Nahrwold, Norbert SewaldAbstract:Cryptophycins are a family of highly cytotoxic, cyclic depsipeptides. They display antitumour activity that is largely maintained for multidrug-resistant tumour cells. Cryptophycins are composed of four building blocks (units A-D) that correspond to the respective amino and hydroxy acids. A new synthetic route to unit A allows the selective generation of all four stereogenic centres in a short, efficient and reliable synthesis and contributes to an easier and faster synthesis of Cryptophycins. The first two stereogenic centres are introduced by a catalytic asymmetric dihydroxylation, whereas the remaining two stereogenic centres are introduced with substrate control of diastereoselectivity. The stereogenic diol function also serves as the epoxide precursor. The approach was used to synthesise the native unit A building block as well as three para-alkoxymethyl analogues from which Cryptophycin-52 and three analogous Cryptophycins were prepared. Macro-cyclisation of the seco-depsipeptides was based on ring-closing metathesis.