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Amos B Smith - One of the best experts on this subject based on the ideXlab platform.
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improved dose response relationship of Discodermolide taxol hybrid congeners
Journal of Natural Products, 2018Co-Authors: Celine Nadaradjane, Amos B Smith, Susan Band Horwitz, Chia Ping Huang Yang, Alicia G Rodriguezgabin, Kenny Ye, Keizo Sugasawa, Onur Atasoylu, Hayley M McdaidAbstract:(+)-Discodermolide is a microtubule-stabilizing agent with potential for the treatment of taxol-refractory malignancies. (+)-Discodermolide congeners containing the C-3′-phenyl side chain of taxol (paclitaxel) were synthesized based on computational docking models predicting this moiety would fill an aromatic pocket of β-tubulin insufficiently occupied by (+)-Discodermolide, thereby conferring improved ligand–target interaction. It was recently demonstrated, however, that the C-3′-phenyl side chain occupied a different space, instead extending toward the M-loop of β-tubulin, where it induced a helical conformation, hypothesized to improve lateral contacts between adjacent microtubule protofilaments. This insight led us to evaluate the biological activity of hybrid congeners using a panel of genetically diverse cancer cell lines. Hybrid molecules retained the same tubulin-polymerizing profile as (+)-Discodermolide. Since (+)-Discodermolide is a potent inducer of accelerated senescence, a fate that contribu...
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Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners
Journal of Natural Products, 2018Co-Authors: Celine Nadaradjane, Amos B Smith, Susan Band Horwitz, Chia Ping Huang Yang, Kenny Ye, Keizo Sugasawa, Onur Atasoylu, Alicia G. Rodriguez-gabin, Hayley M McdaidAbstract:(+)-Discodermolide is a microtubule-stabilizing agent with potential for the treatment of taxol-refractory malignancies. (+)-Discodermolide congeners containing the C-3′-phenyl side chain of taxol (paclitaxel) were synthesized based on computational docking models predicting this moiety would fill an aromatic pocket of β-tubulin insufficiently occupied by (+)-Discodermolide, thereby conferring improved ligand–target interaction. It was recently demonstrated, however, that the C-3′-phenyl side chain occupied a different space, instead extending toward the M-loop of β-tubulin, where it induced a helical conformation, hypothesized to improve lateral contacts between adjacent microtubule protofilaments. This insight led us to evaluate the biological activity of hybrid congeners using a panel of genetically diverse cancer cell lines. Hybrid molecules retained the same tubulin-polymerizing profile as (+)-Discodermolide. Since (+)-Discodermolide is a potent inducer of accelerated senescence, a fate that contribu...
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Abstract 2789: Interaction of (+)-Discodermolide-Taxol hybrids with microtubules
Cancer Research, 2012Co-Authors: Chiaping H Yang, Amos B Smith, Keizo Sugasawa, Onur Atasoylu, Susan Band HorwitzAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Taxol and Discodermolide are both microtubule stabilizing agents that bind to the β-tubulin subunit of microtubules. Based on our results that the hydrophobic binding pocket of β-tubulin is occupied by the Taxol side chain but not by (+)-Discodermolide, and that the two drugs act synergistically in cancer cell lines, a small library of (+)-Discodermolide-Taxol hybrids was synthesized (J. Med. Chem. 54:6319, 2011). Cytotoxicity assays demonstrated a 2-9-fold increase in antiproliferative activity by the hybrids compared to Discodermolide in the human cancer cell lines, A549 and MCF-7. Hybrids containing a tether of 3 carbons that connect Discodermolide with the Taxol side chain, exhibited the best activity. Tubulin assembly assays were performed with the two most potent hybrid molecules. Like Discodermolide, these two hybrids increased tubulin assembly rapidly without a lag period. Tubulin polymerization studies using purified bovine brain tubulin demonstrated that they also had the greatest effect on the formation of polymerized microtubules. These results also were observed in intact A549 cells and in 100,000 x g supernatants prepared from these cells. We have previously shown that [3H]2-(m-azidobenzoyl)Taxol photolabels a peptide containing amino acid residues 217-231 of β-tubulin. A 5-fold molar excess of unlabeled compound inhibited the photolabeling of purified bovine brain tubulin by 94%, demonstrating the specificity of this photolabeling. Microtubule stabilizing agents (MSAs), such as Taxol, epothilone B, Discodermolide and ixabepilone, each at a 5-fold molar excess, inhibited the photolabeling by 24%, 92%, 100% and 41%, respectively, indicating that Discodermolide is the most potent inhibitor of the photolabeling. In contrast, two other MSAs, laulimalide and peloruside that are known to bind to a different site in β-tubulin, exhibited stimulatory effects on the photolabeling. Both drugs, at a 5-fold molar excess, increased the labeling by 30-40%. [3H]2-(m-azidobenzoyl)Taxol (0.5 - 20 µM) was used to study the kinetics of the inhibitory effects of the hybrid molecules on photoaffinity labeling of tubulin. Discodermolide-Taxol hybrids inhibited the photolabeling of bovine brain tubulin in a dose dependent manner. The concentrations that inhibited by 50% were lowest for the two most potent hybrid molecules. Therefore, the tubulin polymerization activity and the binding affinity of the hybrids to β-tubulin correlated with their antiproliferative activity. Other biological properties of the Discodermolide-Taxol hybrids including senescence and antitumor activity are being evaluated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2789. doi:1538-7445.AM2012-2789
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abstract 2789 interaction of Discodermolide taxol hybrids with microtubules
Cancer Research, 2012Co-Authors: Chiaping H Yang, Amos B Smith, Keizo Sugasawa, Onur Atasoylu, Susan Band HorwitzAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Taxol and Discodermolide are both microtubule stabilizing agents that bind to the β-tubulin subunit of microtubules. Based on our results that the hydrophobic binding pocket of β-tubulin is occupied by the Taxol side chain but not by (+)-Discodermolide, and that the two drugs act synergistically in cancer cell lines, a small library of (+)-Discodermolide-Taxol hybrids was synthesized (J. Med. Chem. 54:6319, 2011). Cytotoxicity assays demonstrated a 2-9-fold increase in antiproliferative activity by the hybrids compared to Discodermolide in the human cancer cell lines, A549 and MCF-7. Hybrids containing a tether of 3 carbons that connect Discodermolide with the Taxol side chain, exhibited the best activity. Tubulin assembly assays were performed with the two most potent hybrid molecules. Like Discodermolide, these two hybrids increased tubulin assembly rapidly without a lag period. Tubulin polymerization studies using purified bovine brain tubulin demonstrated that they also had the greatest effect on the formation of polymerized microtubules. These results also were observed in intact A549 cells and in 100,000 x g supernatants prepared from these cells. We have previously shown that [3H]2-(m-azidobenzoyl)Taxol photolabels a peptide containing amino acid residues 217-231 of β-tubulin. A 5-fold molar excess of unlabeled compound inhibited the photolabeling of purified bovine brain tubulin by 94%, demonstrating the specificity of this photolabeling. Microtubule stabilizing agents (MSAs), such as Taxol, epothilone B, Discodermolide and ixabepilone, each at a 5-fold molar excess, inhibited the photolabeling by 24%, 92%, 100% and 41%, respectively, indicating that Discodermolide is the most potent inhibitor of the photolabeling. In contrast, two other MSAs, laulimalide and peloruside that are known to bind to a different site in β-tubulin, exhibited stimulatory effects on the photolabeling. Both drugs, at a 5-fold molar excess, increased the labeling by 30-40%. [3H]2-(m-azidobenzoyl)Taxol (0.5 - 20 µM) was used to study the kinetics of the inhibitory effects of the hybrid molecules on photoaffinity labeling of tubulin. Discodermolide-Taxol hybrids inhibited the photolabeling of bovine brain tubulin in a dose dependent manner. The concentrations that inhibited by 50% were lowest for the two most potent hybrid molecules. Therefore, the tubulin polymerization activity and the binding affinity of the hybrids to β-tubulin correlated with their antiproliferative activity. Other biological properties of the Discodermolide-Taxol hybrids including senescence and antitumor activity are being evaluated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2789. doi:1538-7445.AM2012-2789
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design and synthesis of Discodermolide paclitaxel hybrids leading to enhanced biological activity
Journal of Medicinal Chemistry, 2011Co-Authors: Amos B Smith, Chia Ping Huang Yang, Keizo Sugasawa, Onur Atasoylu, Susan Band HorwitzAbstract:Potential binding modes of (+)-Discodermolide at the paclitaxel binding site of tubulin have been identified by computational studies based on earlier structural and SAR data. Examination of the prospective binding modes reveal that the aromatic pocket occupied by the paclitaxel side chain is unoccupied by (+)-Discodermolide. Based on these findings, a small library of (+)-Discodermolide–paclitaxel hybrids have been designed and synthesized. Biological evaluation reveals a two- to eight-fold increase in antiproliferative activity compared to the parent molecule using the A549 and MCF-7 cancer cell lines.
Susan Band Horwitz - One of the best experts on this subject based on the ideXlab platform.
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improved dose response relationship of Discodermolide taxol hybrid congeners
Journal of Natural Products, 2018Co-Authors: Celine Nadaradjane, Amos B Smith, Susan Band Horwitz, Chia Ping Huang Yang, Alicia G Rodriguezgabin, Kenny Ye, Keizo Sugasawa, Onur Atasoylu, Hayley M McdaidAbstract:(+)-Discodermolide is a microtubule-stabilizing agent with potential for the treatment of taxol-refractory malignancies. (+)-Discodermolide congeners containing the C-3′-phenyl side chain of taxol (paclitaxel) were synthesized based on computational docking models predicting this moiety would fill an aromatic pocket of β-tubulin insufficiently occupied by (+)-Discodermolide, thereby conferring improved ligand–target interaction. It was recently demonstrated, however, that the C-3′-phenyl side chain occupied a different space, instead extending toward the M-loop of β-tubulin, where it induced a helical conformation, hypothesized to improve lateral contacts between adjacent microtubule protofilaments. This insight led us to evaluate the biological activity of hybrid congeners using a panel of genetically diverse cancer cell lines. Hybrid molecules retained the same tubulin-polymerizing profile as (+)-Discodermolide. Since (+)-Discodermolide is a potent inducer of accelerated senescence, a fate that contribu...
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Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners
Journal of Natural Products, 2018Co-Authors: Celine Nadaradjane, Amos B Smith, Susan Band Horwitz, Chia Ping Huang Yang, Kenny Ye, Keizo Sugasawa, Onur Atasoylu, Alicia G. Rodriguez-gabin, Hayley M McdaidAbstract:(+)-Discodermolide is a microtubule-stabilizing agent with potential for the treatment of taxol-refractory malignancies. (+)-Discodermolide congeners containing the C-3′-phenyl side chain of taxol (paclitaxel) were synthesized based on computational docking models predicting this moiety would fill an aromatic pocket of β-tubulin insufficiently occupied by (+)-Discodermolide, thereby conferring improved ligand–target interaction. It was recently demonstrated, however, that the C-3′-phenyl side chain occupied a different space, instead extending toward the M-loop of β-tubulin, where it induced a helical conformation, hypothesized to improve lateral contacts between adjacent microtubule protofilaments. This insight led us to evaluate the biological activity of hybrid congeners using a panel of genetically diverse cancer cell lines. Hybrid molecules retained the same tubulin-polymerizing profile as (+)-Discodermolide. Since (+)-Discodermolide is a potent inducer of accelerated senescence, a fate that contribu...
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abstract 2789 interaction of Discodermolide taxol hybrids with microtubules
Cancer Research, 2012Co-Authors: Chiaping H Yang, Amos B Smith, Keizo Sugasawa, Onur Atasoylu, Susan Band HorwitzAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Taxol and Discodermolide are both microtubule stabilizing agents that bind to the β-tubulin subunit of microtubules. Based on our results that the hydrophobic binding pocket of β-tubulin is occupied by the Taxol side chain but not by (+)-Discodermolide, and that the two drugs act synergistically in cancer cell lines, a small library of (+)-Discodermolide-Taxol hybrids was synthesized (J. Med. Chem. 54:6319, 2011). Cytotoxicity assays demonstrated a 2-9-fold increase in antiproliferative activity by the hybrids compared to Discodermolide in the human cancer cell lines, A549 and MCF-7. Hybrids containing a tether of 3 carbons that connect Discodermolide with the Taxol side chain, exhibited the best activity. Tubulin assembly assays were performed with the two most potent hybrid molecules. Like Discodermolide, these two hybrids increased tubulin assembly rapidly without a lag period. Tubulin polymerization studies using purified bovine brain tubulin demonstrated that they also had the greatest effect on the formation of polymerized microtubules. These results also were observed in intact A549 cells and in 100,000 x g supernatants prepared from these cells. We have previously shown that [3H]2-(m-azidobenzoyl)Taxol photolabels a peptide containing amino acid residues 217-231 of β-tubulin. A 5-fold molar excess of unlabeled compound inhibited the photolabeling of purified bovine brain tubulin by 94%, demonstrating the specificity of this photolabeling. Microtubule stabilizing agents (MSAs), such as Taxol, epothilone B, Discodermolide and ixabepilone, each at a 5-fold molar excess, inhibited the photolabeling by 24%, 92%, 100% and 41%, respectively, indicating that Discodermolide is the most potent inhibitor of the photolabeling. In contrast, two other MSAs, laulimalide and peloruside that are known to bind to a different site in β-tubulin, exhibited stimulatory effects on the photolabeling. Both drugs, at a 5-fold molar excess, increased the labeling by 30-40%. [3H]2-(m-azidobenzoyl)Taxol (0.5 - 20 µM) was used to study the kinetics of the inhibitory effects of the hybrid molecules on photoaffinity labeling of tubulin. Discodermolide-Taxol hybrids inhibited the photolabeling of bovine brain tubulin in a dose dependent manner. The concentrations that inhibited by 50% were lowest for the two most potent hybrid molecules. Therefore, the tubulin polymerization activity and the binding affinity of the hybrids to β-tubulin correlated with their antiproliferative activity. Other biological properties of the Discodermolide-Taxol hybrids including senescence and antitumor activity are being evaluated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2789. doi:1538-7445.AM2012-2789
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Abstract 2789: Interaction of (+)-Discodermolide-Taxol hybrids with microtubules
Cancer Research, 2012Co-Authors: Chiaping H Yang, Amos B Smith, Keizo Sugasawa, Onur Atasoylu, Susan Band HorwitzAbstract:Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Taxol and Discodermolide are both microtubule stabilizing agents that bind to the β-tubulin subunit of microtubules. Based on our results that the hydrophobic binding pocket of β-tubulin is occupied by the Taxol side chain but not by (+)-Discodermolide, and that the two drugs act synergistically in cancer cell lines, a small library of (+)-Discodermolide-Taxol hybrids was synthesized (J. Med. Chem. 54:6319, 2011). Cytotoxicity assays demonstrated a 2-9-fold increase in antiproliferative activity by the hybrids compared to Discodermolide in the human cancer cell lines, A549 and MCF-7. Hybrids containing a tether of 3 carbons that connect Discodermolide with the Taxol side chain, exhibited the best activity. Tubulin assembly assays were performed with the two most potent hybrid molecules. Like Discodermolide, these two hybrids increased tubulin assembly rapidly without a lag period. Tubulin polymerization studies using purified bovine brain tubulin demonstrated that they also had the greatest effect on the formation of polymerized microtubules. These results also were observed in intact A549 cells and in 100,000 x g supernatants prepared from these cells. We have previously shown that [3H]2-(m-azidobenzoyl)Taxol photolabels a peptide containing amino acid residues 217-231 of β-tubulin. A 5-fold molar excess of unlabeled compound inhibited the photolabeling of purified bovine brain tubulin by 94%, demonstrating the specificity of this photolabeling. Microtubule stabilizing agents (MSAs), such as Taxol, epothilone B, Discodermolide and ixabepilone, each at a 5-fold molar excess, inhibited the photolabeling by 24%, 92%, 100% and 41%, respectively, indicating that Discodermolide is the most potent inhibitor of the photolabeling. In contrast, two other MSAs, laulimalide and peloruside that are known to bind to a different site in β-tubulin, exhibited stimulatory effects on the photolabeling. Both drugs, at a 5-fold molar excess, increased the labeling by 30-40%. [3H]2-(m-azidobenzoyl)Taxol (0.5 - 20 µM) was used to study the kinetics of the inhibitory effects of the hybrid molecules on photoaffinity labeling of tubulin. Discodermolide-Taxol hybrids inhibited the photolabeling of bovine brain tubulin in a dose dependent manner. The concentrations that inhibited by 50% were lowest for the two most potent hybrid molecules. Therefore, the tubulin polymerization activity and the binding affinity of the hybrids to β-tubulin correlated with their antiproliferative activity. Other biological properties of the Discodermolide-Taxol hybrids including senescence and antitumor activity are being evaluated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2789. doi:1538-7445.AM2012-2789
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design and synthesis of Discodermolide paclitaxel hybrids leading to enhanced biological activity
Journal of Medicinal Chemistry, 2011Co-Authors: Amos B Smith, Chia Ping Huang Yang, Keizo Sugasawa, Onur Atasoylu, Susan Band HorwitzAbstract:Potential binding modes of (+)-Discodermolide at the paclitaxel binding site of tubulin have been identified by computational studies based on earlier structural and SAR data. Examination of the prospective binding modes reveal that the aromatic pocket occupied by the paclitaxel side chain is unoccupied by (+)-Discodermolide. Based on these findings, a small library of (+)-Discodermolide–paclitaxel hybrids have been designed and synthesized. Biological evaluation reveals a two- to eight-fold increase in antiproliferative activity compared to the parent molecule using the A549 and MCF-7 cancer cell lines.
Ian Paterson - One of the best experts on this subject based on the ideXlab platform.
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Induction of accelerated senescence by the microtubule-stabilizing agent peloruside A
Investigational New Drugs, 2017Co-Authors: Ariane Chan, Connie Gilfillan, Nikki Templeton, Ian Paterson, Peter T. Northcote, John H. MillerAbstract:Chemotherapeutic agents can induce accelerated senescence in tumor cells, an irreversible state of cell cycle arrest. Paclitaxel, a microtubule-stabilizing agent used to treat solid tumors of the breast, ovary, and lung and Discodermolide, another stabilizing agent from a marine sponge, induce senescence in cultured cancer cells. The aim of this study was to determine if the microtubule-stabilizing agent peloruside A, a polyketide natural product from a marine sponge, can induce accelerated senescence in a breast cancer cell line MCF7. Doxorubicin, a DNA-damaging agent, paclitaxel, and Discodermolide were used as positive controls. Senescence-associated-β-galactosidase activity was increased by peloruside A, similar to paclitaxel, discodermolde, and doxorubicin, with a potency heirarchy of doxorubicin > paclitaxel > Discodermolide > peloruside, based on IC_25 concentrations that inhibit proliferation. Clonogenic survival was significantly decreased by peloruside A, similar to doxorubicin and the two other microtubule-stabilizing agents. The tumor suppressor protein p53 increased after treatment, whereas pRb decreased in response to all four compounds. It was concluded that in addition to apoptosis, peloruside A causes accelerated senescence in a subpopulation of MCF7 cells that contributes to its potential anticancer activity in a breast cancer cell line.
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insights into the interaction of Discodermolide and docetaxel with tubulin mapping the binding sites of microtubule stabilizing agents by using an integrated nmr and computational approach
ACS Chemical Biology, 2011Co-Authors: Angeles Canales, Ian Paterson, Javier Rodriguezsalarichs, Chiara Trigili, Lidia Nieto, Claire Coderch, Jose Manuel Andreu, Jesus Jimenezbarbero, Jose Fernando DiazAbstract:The binding interactions of two antitumor agents that target the paclitaxel site, docetaxel and Discodermolide, to unassembled α/β-tubulin heterodimers and microtubules have been studied using biochemical and NMR techniques. The use of Discodermolide as a water-soluble paclitaxel biomimetic and extensive NMR experiments allowed the detection of binding of microtubule-stabilizing agents to unassembled tubulin α/β-heterodimers. The bioactive 3D structures of docetaxel and Discodermolide bound to α/β-heterodimers were elucidated and compared to those bound to microtubules, where subtle changes in the conformations of docetaxel in its different bound states were evident. Moreover, the combination of experimental TR-NOE and STD NMR data with CORCEMA-ST calculations indicate that docetaxel and Discodermolide target an additional binding site at the pore of the microtubules, which is different from the internal binding site at the lumen previously determined by electron crystallography. Binding to this pore site...
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total synthesis and biological evaluation of a series of macrocyclic hybrids and analogues of the antimitotic natural products dictyostatin Discodermolide and taxol
Chemistry-an Asian Journal, 2011Co-Authors: Ian Paterson, Guy J Naylor, Nicola M Gardner, Esther A Guzman, Amy E WrightAbstract:The design, synthesis, and biological evaluation of a series of hybrids and analogues of the microtubule-stabilizing anticancer agents dictyostatin, Discodermolide, and taxol is described. A 22-membered macrolide scaffold was prepared by adapting earlier synthetic routes directed towards dictyostatin and Discodermolide, taking advantage of the distinctive structural and stereochemical similarities between these two polyketide-derived marine natural products. Initial endeavors towards accessing novel Discodermolide/dictyostatin hybrids led to the adoption of a late-stage diversification strategy and the construction of a small library of methyl-ether derivatives, along with the first triple hybrids bearing the side-chain of taxol or taxotere attached through an ester linkage. Biological assays of the anti-proliferative activity of these compounds in a series of human cancer cell lines, including the taxol-resistant NCI/ADR-Res cell line, allowed the proposal of various structure-activity relationships. This led to the identification of a potent macrocyclic Discodermolide/dictyostatin hybrid 12 and its C9 methoxy derivative 38, accessible by an efficient total synthesis and with a similar biological profile to dictyostatin.
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total synthesis of a potent hybrid of the anticancer natural products dictyostatin and Discodermolide
Chemical Communications, 2008Co-Authors: Ian Paterson, Guy J Naylor, Amy E WrightAbstract:A potent dictyostatin–Discodermolide hybrid was designed and synthesised; it showed enhanced cell growth inhibitory activity relative to Discodermolide in four human cancer cell lines including the Taxol-resistant NCI/ADR-Res cell line.
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development of practical syntheses of the marine anticancer agents Discodermolide and dictyostatin
Natural Product Reports, 2008Co-Authors: Gordon J Florence, Nicola M Gardner, Ian PatersonAbstract:Covering: 1993 to 2007 Initially isolated in trace quantities from deep-sea sponges, the structurally related polyketides Discodermolide and dictyostatin share the same microtubule-stabilizing antimitotic mechanism as Taxol. Discodermolide has been the focus of intense research activity in order to develop a practical supply route, and these efforts ultimately allowed its large-scale synthesis and the initiation of clinical trials as a novel anticancer drug. Similarly, the re-isolation and synthesis of dictyostatin continues to stimulate the biological and chemical communities in their quest for the development of new chemotherapeutic agents. This comprehensive review chronicles the synthetic endeavours undertaken over the last 15 years towards the development and realization of practical chemical syntheses of Discodermolide and, more recently, dictyostatin, focusing on the methods and strategies employed for achieving overall stereocontrol and key fragment unions, as well as the design and synthesis of novel hybrid structures.
Ross E Longley - One of the best experts on this subject based on the ideXlab platform.
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Semisynthetic analogues of the microtubule-stabilizing agent Discodermolide: preparation and biological activity.
Journal of natural products, 2020Co-Authors: Sarath P Gunasekera, Ross E Longley, Richard A IsbruckerAbstract:A series of 12 semisynthetic Discodermolide analogues, 2-13, have been prepared using natural (+)-Discodermolide (1) and evaluated for in vitro cytotoxicity against cultured murine P-388 leukemia and A-549 human adenocarcinoma cells. These semisynthetic analogues showed a significant variation of cytotoxicity and confirmed the importance of the C-7 through C-19 molecular fragment for potency. Specifically, these analogues suggested the importance of the C-11 and C-17 hydroxyl groups and the C-13 double bond for the potency of Discodermolide. The preparation, structure elucidation, and biological activity of these new analogues are described.
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Discodermolide: Past, Present, and Future
Natural Products and Cancer Drug Discovery, 2012Co-Authors: Ross E LongleyAbstract:(+)-Discodermolide, a polyhydroxylated lactone isolated from the marine sponge Discodermia dissoluta, is a promising antitumor agent that continues to be the subject of intensive chemical, biological, and pharmaceutical research since its discovery two decades ago. Although structurally distinct from taxol, Discodermolide shares a common mechanism of action as a potent tubulin polymerizer, resulting in blockage of cells in the G2/M phase of the cell cycle, aberrant microtubule function, and cell death. Following its licensing from Harbor Branch Oceanographic Institution in 1998 by Novartis AG as an antitumor agent, Discodermolide was afforded an unprecedented priority status for synthesis on an industrial scale, borrowing and modifying in some cases, academic synthetic schemes to produce quantities sufficient for clinical trial. From a co-discoverer’s viewpoint, the story of Discodermolide will be described here, starting with its discovery, its progression through preclinical evaluation, highlights from the synthetic contributions of academia and industry, a brief SAR walk around the molecule, the results of the first clinical trial and the more recent journey from the actual compound, through its various analogs and finally to its evolution to some exciting novel “hybrid” molecules.
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immunosuppression by Discodermolide
Annals of the New York Academy of Sciences, 2006Co-Authors: Ross E Longley, Sarath P Gunasekera, Denise A Faherty, John A Mclane, Francis J DumontAbstract:: In summary, Discodermolide, a novel, marine-derived compound, is a potent in vitro and in vivo immunosuppressive agent. Discodermolide blocks cellular proliferation in lymphoid and nonlymphoid cells. This blocking action is not due to cytotoxicity. Blockage of cell proliferation by Discodermolide appears to occur at the G2/M interface of the cell cycle, similar to that observed with other types of antiproliferative drugs (i.e., doxorubicin). The cell cycle block appears to be reversible, as cells recover normal cycling patterns within 48 h after removal of the compound. Additional work with this compound is targeted towards determining the exact nature of Discodermolide's mitotic block and is currently under way.
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five new Discodermolide analogues from the marine sponge discodermia species
Journal of Natural Products, 2002Co-Authors: Sarath P Gunasekera, Ross E Longley, Richard A Isbrucker, Gopal K Paul, Shirley A PomponiAbstract:Discodermolide (1) and five new Discodermolide analogues trivially named 2-epi-Discodermolide (2), 2-des-methylDiscodermolide (3), 5-hydroxymethyldiscodermolate (4), 19-des-aminocarbonylDiscodermolide (5), and 9(13)-cycloDiscodermolide (6) have been isolated from marine sponges belonging to the genus Discodermia collected from the Caribbean Sea. The isolation, structure elucidation, and biological activities of 2−6 are described. The natural analogues, which were isolated in trace amounts, exhibited significant variation of cytotoxicity against the cultured murine P-388 leukemia and A-549 human adenocarcinoma cells and suggested the importance of the C7 through C17 moiety for potency against cultured tumor cell lines.
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structure activity relationship studies of Discodermolide and its semisynthetic acetylated analogs on microtubule function and cytotoxicity
Cancer Chemotherapy and Pharmacology, 2001Co-Authors: Richard A Isbrucker, Sarath P Gunasekera, Ross E LongleyAbstract:Purpose: Discodermolide, a natural product from the marine sponge Discodermia dissoluta, has been previously described as an antimitotic agent with microtubule hyperstabilizing properties similar to those of paclitaxel (Taxol). The clinical success of paclitaxel has led to a growing interest in novel antimitotic compounds and the elucidation of their structure-activity characteristics. Analogs of Discodermolide were prepared by acetylation of the hydroxyl groups at carbons 3, 7, 11 and/or 17 and tested for biological activity in human tumor cells to determine the structural requirements for tubulin interaction and cytotoxic effects. Methods: A549 human lung adenocarcinoma cells were incubated with Discodermolide, or its acetylated analogs, and examined for their effects on microtubule architecture, cytotoxicity, and perturbations of the cell cycle. To confirm their direct interaction with tubulin, analogs were assayed for their ability to induce the polymerization of purified bovine brain tubulin. Results: Acetylation of Discodermolide at the C-7 hydroxyl group potentiated the cytotoxicity of the molecule to A549 cells, whereas acetylation at the C-3 hydroxyl group had little effect on the cytotoxicity of the parent or C-7-acetylated compounds. The acetylation of the hydroxyl groups at the C-11 and C-17 positions severely abrogated the cytotoxicity of the molecule. Cell cycle analysis by flow cytometry revealed that the more cytotoxic analogs caused the accumulation of cells in the G2/M phase, a mechanism previously reported for Discodermolide. All Discodermolide analogs with IC50 values below 1000 nM exhibited microtubule effects to varying degrees in cultured A549 cells, yet only the most cytotoxic promoted the polymerization of purified tubulin. Conclusions: Although the parent compound was more effective at polymerizing purified tubulin, acetylation of the C-3 or C-3 and C-7 hydroxyl groups improved its cytotoxicity in whole cells suggesting that acetylation either enhances accumulation of the molecules within cells or imparts a secondary cytotoxic quality not present in the Discodermolide molecule. The study reported here is the first to provide information on the structure-activity relationships of Discodermolide using human tumor cells and analogs produced by semisynthetic modification of natural Discodermolide.
Sarath P Gunasekera - One of the best experts on this subject based on the ideXlab platform.
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Semisynthetic analogues of the microtubule-stabilizing agent Discodermolide: preparation and biological activity.
Journal of natural products, 2020Co-Authors: Sarath P Gunasekera, Ross E Longley, Richard A IsbruckerAbstract:A series of 12 semisynthetic Discodermolide analogues, 2-13, have been prepared using natural (+)-Discodermolide (1) and evaluated for in vitro cytotoxicity against cultured murine P-388 leukemia and A-549 human adenocarcinoma cells. These semisynthetic analogues showed a significant variation of cytotoxicity and confirmed the importance of the C-7 through C-19 molecular fragment for potency. Specifically, these analogues suggested the importance of the C-11 and C-17 hydroxyl groups and the C-13 double bond for the potency of Discodermolide. The preparation, structure elucidation, and biological activity of these new analogues are described.
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immunosuppression by Discodermolide
Annals of the New York Academy of Sciences, 2006Co-Authors: Ross E Longley, Sarath P Gunasekera, Denise A Faherty, John A Mclane, Francis J DumontAbstract:: In summary, Discodermolide, a novel, marine-derived compound, is a potent in vitro and in vivo immunosuppressive agent. Discodermolide blocks cellular proliferation in lymphoid and nonlymphoid cells. This blocking action is not due to cytotoxicity. Blockage of cell proliferation by Discodermolide appears to occur at the G2/M interface of the cell cycle, similar to that observed with other types of antiproliferative drugs (i.e., doxorubicin). The cell cycle block appears to be reversible, as cells recover normal cycling patterns within 48 h after removal of the compound. Additional work with this compound is targeted towards determining the exact nature of Discodermolide's mitotic block and is currently under way.
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five new Discodermolide analogues from the marine sponge discodermia species
Journal of Natural Products, 2002Co-Authors: Sarath P Gunasekera, Ross E Longley, Richard A Isbrucker, Gopal K Paul, Shirley A PomponiAbstract:Discodermolide (1) and five new Discodermolide analogues trivially named 2-epi-Discodermolide (2), 2-des-methylDiscodermolide (3), 5-hydroxymethyldiscodermolate (4), 19-des-aminocarbonylDiscodermolide (5), and 9(13)-cycloDiscodermolide (6) have been isolated from marine sponges belonging to the genus Discodermia collected from the Caribbean Sea. The isolation, structure elucidation, and biological activities of 2−6 are described. The natural analogues, which were isolated in trace amounts, exhibited significant variation of cytotoxicity against the cultured murine P-388 leukemia and A-549 human adenocarcinoma cells and suggested the importance of the C7 through C17 moiety for potency against cultured tumor cell lines.
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structure activity relationship studies of Discodermolide and its semisynthetic acetylated analogs on microtubule function and cytotoxicity
Cancer Chemotherapy and Pharmacology, 2001Co-Authors: Richard A Isbrucker, Sarath P Gunasekera, Ross E LongleyAbstract:Purpose: Discodermolide, a natural product from the marine sponge Discodermia dissoluta, has been previously described as an antimitotic agent with microtubule hyperstabilizing properties similar to those of paclitaxel (Taxol). The clinical success of paclitaxel has led to a growing interest in novel antimitotic compounds and the elucidation of their structure-activity characteristics. Analogs of Discodermolide were prepared by acetylation of the hydroxyl groups at carbons 3, 7, 11 and/or 17 and tested for biological activity in human tumor cells to determine the structural requirements for tubulin interaction and cytotoxic effects. Methods: A549 human lung adenocarcinoma cells were incubated with Discodermolide, or its acetylated analogs, and examined for their effects on microtubule architecture, cytotoxicity, and perturbations of the cell cycle. To confirm their direct interaction with tubulin, analogs were assayed for their ability to induce the polymerization of purified bovine brain tubulin. Results: Acetylation of Discodermolide at the C-7 hydroxyl group potentiated the cytotoxicity of the molecule to A549 cells, whereas acetylation at the C-3 hydroxyl group had little effect on the cytotoxicity of the parent or C-7-acetylated compounds. The acetylation of the hydroxyl groups at the C-11 and C-17 positions severely abrogated the cytotoxicity of the molecule. Cell cycle analysis by flow cytometry revealed that the more cytotoxic analogs caused the accumulation of cells in the G2/M phase, a mechanism previously reported for Discodermolide. All Discodermolide analogs with IC50 values below 1000 nM exhibited microtubule effects to varying degrees in cultured A549 cells, yet only the most cytotoxic promoted the polymerization of purified tubulin. Conclusions: Although the parent compound was more effective at polymerizing purified tubulin, acetylation of the C-3 or C-3 and C-7 hydroxyl groups improved its cytotoxicity in whole cells suggesting that acetylation either enhances accumulation of the molecules within cells or imparts a secondary cytotoxic quality not present in the Discodermolide molecule. The study reported here is the first to provide information on the structure-activity relationships of Discodermolide using human tumor cells and analogs produced by semisynthetic modification of natural Discodermolide.
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synthetic analogues of the microtubule stabilizing agent Discodermolide preparation and biological activity
Journal of Natural Products, 2001Co-Authors: Sarath P Gunasekera, Ross E Longley, Richard A IsbruckerAbstract:A series of eight Discodermolide acetates have been prepared using natural (+)-Discodermolide and evaluated for in vitro cytotoxicity against the cultured murine P-388 leukemia cells. The acetylated analogues showed a significant variation of cytotoxicity and suggested the importance of C-11 and C-17 hydroxyl groups for potency. The preparation and structure elucidation of the new analogues are described.