The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Richard E Honkanen - One of the best experts on this subject based on the ideXlab platform.
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suppression of ser thr phosphatase 4 pp4c ppp4c mimics a novel post mitotic action of Fostriecin producing mitotic slippage followed by tetraploid cell death
Molecular Cancer Research, 2013Co-Authors: Benjamin Theobald, Kathy Bonness, Alla Musiyenko, Joel Andrews, Gudrun Urban, Xizhong Huang, Nicholas M Dean, Richard E HonkanenAbstract:Fostriecin is a natural product purified from Sterptomyces extracts with antitumor activity sufficient to warrant human clinical trials. Unfortunately, difficulties associated with supply and stable drug formulation stalled further development. At a molecular level, Fostriecin is known to act as a catalytic inhibitor of four PPP-family-phosphatases, and reports describing the syntheses of designed molecules in the class suggest derivatives targeting enzymes within the Fostriecin sensitive sub-family can be produced. However, it is not clear if the tumor selective cytotoxicity of Fostriecin results from the inhibition of a specific phosphatase, multiple phosphatases, or a limited subset of Fostriecin sensitive phosphatases. How the inhibition of sensitive phosphatases contributes to tumor selective cytotoxicity is also not clear. Here, high-content time-lapse imaging of live cells reveals novel insight into the cellular actions of Fostriecin, showing that Fostriecin induced apoptosis is not simply induced following a sustained mitotic arrest. Rather, apoptosis occurs in an apparent second interphase produced when tetraploid cells undergo mitotic slippage. Comparison of the actions of Fostriecin and antisense-oligonucleotides specifically targeting human Fostriecin-sensitive phosphatases revealed that the suppression PP4C alone is sufficient to mimic many actions of Fostriecin. Importantly, antisense-oligonucleotides targeting PP4C induce apoptosis, with death occurring in tetraploid cells produced following mitotic slippage. This affect was not observed following the suppression of PP1C, PP2AC or PP5C. Although future studies are needed to clarify how the suppression of PP4C triggers mitotic slippage/apoptosis, our observations suggest further development of Fostriecin class inhibitors should consider PP4C as a potentially important target.
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structure activity relationship studies of Fostriecin cytostatin and key analogs with pp1 pp2a pp5 and β12 β13 chimeras pp1 pp2a and pp5 pp2a provide further insight into the inhibitory actions of Fostriecin family inhibitors
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Mark R Swingle, Dale L Boger, Lauren Amable, Brian G Lawhorn, Suzanne B Buck, Christopher P Burke, Pukar Ratti, Kimberly L Fischer, Richard E HonkanenAbstract:Fostriecin and cytostatin are structurally related natural inhibitors of serine/threonine phosphatases, with promising antitumor activity. The total synthesis of these antitumor agents has enabled the production of structural analogs, which are useful to explore the biological significance of features contained in the parent compounds. Here, the inhibitory activity of Fostriecin, cytostatin, and 10 key structural analogs were tested in side-by-side phosphatase assays to further characterize their inhibitory activity against PP1c (Ser/Thr protein phosphatase 1 catalytic subunit), PP2Ac (Ser/Thr protein phosphatase 2A catalytic subunit), PP5c (Ser/Thr protein phosphatase 5 catalytic subunit), and chimeras of PP1 (Ser/Thr protein phosphatase 1) and PP5 (Ser/Thr protein phosphatase 5), in which key residues predicted for inhibitor contact with PP2A (Ser/Thr protein phosphatase 2A) were introduced into PP1 and PP5 using site-directed mutagenesis. The data confirm the importance of the C9-phosphate and C11-alcohol for general inhibition and further demonstrate the importance of a predicted C3 interaction with a unique cysteine (Cys269) in the β12–β13 loop of PP2A. The data also indicate that additional features beyond the unsaturated lactone contribute to inhibitory potency and selectivity. Notably, a derivative of Fostriecin lacking the entire lactone subunit demonstrated marked potency and selectivity for PP2A, while having substantially reduced and similar activity against PP1 and PP1/PP2A- PP5/PP2A-chimeras that have greatly increased sensitivity to both Fostriecin and cytostatin. This suggests that other features [e.g., the (Z,Z,E)-triene] also contribute to inhibitory selectivity. When considered together with previous data, these studies suggest that, despite the high structural conservation of the catalytic site in PP1, PP2A and PP5, the development of highly selective catalytic inhibitors should be feasible.
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fundamental role of the Fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition
Journal of the American Chemical Society, 2003Co-Authors: Suzanne B Buck, Kathy Bonness, Richard E Honkanen, Satoshi Ichikawa, C M Gauss, Danielle R Soenen, Mark R Swingle, Christophe Hardouin, Inkyu Hwang, Dale L BogerAbstract:Key derivatives and analogues of Fostriecin were prepared and examined that revealed a fundamental role for the unsaturated lactone and confirmed the essential nature of the phosphate monoester. Thus, an identical 200-fold reduction in protein phosphatase 2A (PP2A) inhibition is observed with either the saturated lactone (7) or with an analogue that lacks the entire lactone (15). This 200-fold increase in PP2A inhibition attributable to the unsaturated lactone potentially may be due to reversible C269 alkylation within the PP beta12-beta13 active site loop accounting for PP2A/4 potency and selectivity.
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importance of the β12 β13 loop in protein phosphatase 1 catalytic subunit for inhibition by toxins and mammalian protein inhibitors
Journal of Biological Chemistry, 1999Co-Authors: John H Connor, Richard E Honkanen, Theresa Kleeman, Sailen Barik, Shirish ShenolikarAbstract:Abstract Type-1 protein serine/threonine phosphatases (PP1) are uniquely inhibited by the mammalian proteins, inhibitor-1 (I-1), inhibitor-2 (I-2), and nuclear inhibitor of PP1 (NIPP-1). In addition, several natural compounds inhibit both PP1 and the type-2 phosphatase, PP2A. Deletion of C-terminal sequences that included the β12-β13 loop attenuated the inhibition of the resulting PP1α catalytic core by I-1, I-2, NIPP-1, and several toxins, including tautomycin, microcystin-LR, calyculin A, and okadaic acid. Substitution of C-terminal sequences from the PP2A catalytic subunit produced a chimeric enzyme, CRHM2, that was inhibited by toxins with dose-response characteristics of PP1 and not PP2A. However, CRHM2 was insensitive to the PP1-specific inhibitors, I-1, I-2, and NIPP-1. The anticancer compound, Fostriecin, differed from other phosphatase inhibitors in that it inhibited wild-type PP1α, the PP1α catalytic core, and CRHM2 with identical IC50. Binding of wild-type and mutant phosphatases to immobilized microcystin-LR, NIPP-1, and I-2 established that the β12-β13 loop was essential for the association of PP1 with toxins and the protein inhibitors. These studies point to the importance of the β12-β13 loop structure and conformation for the control of PP1 functions by toxins and endogenous proteins.
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Fostriecin an inhibitor of protein phosphatase 2a limits myocardial infarct size even when administered after onset of ischemia
Circulation, 1998Co-Authors: Christof Weinbrenner, Stephen C Armstrong, Charles E Ganote, Richard E Honkanen, Aimee H Walsh, Christopher P Baines, Guangshung Liu, Michael V Cohen, James M DowneyAbstract:Background—The role of protein phosphatases (PPs) during ischemic preconditioning in the rabbit heart was examined. Methods and Results—Fostriecin, a potent inhibitor of PP2A, was administered to isolated rabbit hearts starting either 15 minutes before or 10 minutes after the onset of a 30-minute period of regional ischemia and continuing until the onset of reperfusion. After 2 hours of reperfusion, infarct size was measured with triphenyltetrazolium chloride. In a second study with isolated rabbit cardiomyocytes, the effect of Fostriecin pretreatment was assessed by measuring changes in cell osmotic fragility during simulated ischemia. PP1 and PP2A activities of isolated control and ischemically preconditioned cells were also measured. In a third series of experiments, left ventricular biopsies of isolated rabbit hearts were obtained before and at selected times during 60 minutes of global ischemia, and the tissue was assayed for PP1 and PP2A activities. In isolated hearts pretreated with Fostriecin, onl...
Mitsuru Shoji - One of the best experts on this subject based on the ideXlab platform.
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formal total synthesis of Fostriecin by 1 4 asymmetric induction with an alkyne cobalt complex
Chemistry: A European Journal, 2010Co-Authors: Yujiro Hayashi, Hirofumi Yamaguchi, Maya Toyoshima, Kotaro Okado, Takumi Toyo, Mitsuru ShojiAbstract:The synthesis of a protected dephosphoFostriecin, and thereby a formal synthesis of Fostriecin, has been accomplished. The synthetic challenges were the construction of four stereogenic centers and the conformationally labile cis-cis-trans-triene moiety. Previous total syntheses have employed at least two asymmetric reactions that required the use of an external chiral auxiliary. Although remote stereoinduction in a 1,4-relationship is considered difficult, we have developed a notable 1,4-asymmetric induction that utilizes an alkyne–cobalt complex for the control of C5 stereochemistry by the C8 stereogenic center. The stereochemistry at C11 was established by 1,3-asymmetric induction with a higher-order alkynyl-zinc reagent. Thus, only one asymmetric reaction requiring an external chiral auxiliary was employed in this route. The labile cis-cis-trans-triene unit was constructed at a late stage of the synthesis by diastereoselective coupling of a dienyne and an aldehyde unit, followed by reduction.
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formal total synthesis of Fostriecin via 1 4 asymmetric induction using cobalt alkyne complex
Organic Letters, 2008Co-Authors: Yujiro Hayashi, Hirofumi Yamaguchi, Maya Toyoshima, Kotaro Okado, Takumi Toyo, Mitsuru ShojiAbstract:The synthesis of a protected dephosphoFostriecin, and thereby a formal synthesis of Fostriecin, has been accomplished. Two of the four chiral centers are controlled by an external chiral auxiliary and the other two are synthesized stereoselectively, one by a novel 1,4-asymmetric induction using cobalt-alkyne complex, and the other by 1,3-asymmetric induction.
Aimee H Walsh - One of the best experts on this subject based on the ideXlab platform.
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Fostriecin an inhibitor of protein phosphatase 2a limits myocardial infarct size even when administered after onset of ischemia
Circulation, 1998Co-Authors: Christof Weinbrenner, Stephen C Armstrong, Charles E Ganote, Richard E Honkanen, Aimee H Walsh, Christopher P Baines, Guangshung Liu, Michael V Cohen, James M DowneyAbstract:Background—The role of protein phosphatases (PPs) during ischemic preconditioning in the rabbit heart was examined. Methods and Results—Fostriecin, a potent inhibitor of PP2A, was administered to isolated rabbit hearts starting either 15 minutes before or 10 minutes after the onset of a 30-minute period of regional ischemia and continuing until the onset of reperfusion. After 2 hours of reperfusion, infarct size was measured with triphenyltetrazolium chloride. In a second study with isolated rabbit cardiomyocytes, the effect of Fostriecin pretreatment was assessed by measuring changes in cell osmotic fragility during simulated ischemia. PP1 and PP2A activities of isolated control and ischemically preconditioned cells were also measured. In a third series of experiments, left ventricular biopsies of isolated rabbit hearts were obtained before and at selected times during 60 minutes of global ischemia, and the tissue was assayed for PP1 and PP2A activities. In isolated hearts pretreated with Fostriecin, onl...
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Fostriecin mediated g2 m phase growth arrest correlates with abnormal centrosome replication the formation of aberrant mitotic spindles and the inhibition of serine threonine protein phosphatase activity
Cancer Research, 1998Co-Authors: Aiyang Cheng, Ron Balczon, Zhuang Zuo, Jamie S Koons, Aimee H Walsh, Richard E HonkanenAbstract:Abstract Fostriecin, a structurally unique phosphate ester, is presently under evaluation in clinical trials to determine its potential use as an antitumor drug in humans. Fostriecin has been reported as having inhibitory activity against DNA topoisomerase type II and protein phosphatases implicated in cell-cycle control. However, the relative contribution of these mechanisms to the antitumor activity of Fostriecin has not yet been elucidated. In this study, after confirming that Fostriecin is a potent inhibitor of serine/threonine protein phosphatase type 2A and a weak inhibitor of serine/threonine protein phosphatase type 1, we show that Fostriecin inhibits ∼50% of the divalent cation independent serine/threonine protein phosphatase (PPase) activity contained in whole cell homogenates of Chinese hamster ovary cells at concentrations associated with antitumor activity (1–20 µm). Investigations into the cellular effects produced by Fostriecin treatment reveal that 1–20 µm Fostriecin induces a dose-dependent arrest of cell growth during the G2-M phase of the cell cycle. Immunostaining of treated cells indicates that growth arrest occurs before the completion of mitosis and that Fostriecin-induced growth arrest is associated with the aberrant amplification of centrosomes, which results in the formation of abnormal mitotic spindles. The “mitotic block” induced by Fostriecin is reversible if treatment is discontinued in
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Fostriecin an antitumor antibiotic with inhibitory activity against serine threonine protein phosphatases types 1 pp1 and 2a pp2a is highly selective for pp2a
FEBS Letters, 1997Co-Authors: Aimee H Walsh, Aiyang Cheng, Richard E HonkanenAbstract:Fostriecin, an antitumor antibiotic produced by Streptomyces pulveraceus, is a strong inhibitor of type 2A (PP2A; IC50 3.2 nM) and a weak inhibitor of type 1 (PP1; IC50 131 μM) serine/threonine protein phosphatases. Fostriecin has no apparent effect on the activity of PP2B, and dose-inhibition studies conducted with whole cell homogenates indicate that Fostriecin also inhibits the native forms of PP1 and PP2A. Studies with recombinant PP1/PP2A chimeras indicate that okadaic acid and Fostriecin have different binding sites.
Dale L Boger - One of the best experts on this subject based on the ideXlab platform.
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structure activity relationship studies of Fostriecin cytostatin and key analogs with pp1 pp2a pp5 and β12 β13 chimeras pp1 pp2a and pp5 pp2a provide further insight into the inhibitory actions of Fostriecin family inhibitors
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Mark R Swingle, Dale L Boger, Lauren Amable, Brian G Lawhorn, Suzanne B Buck, Christopher P Burke, Pukar Ratti, Kimberly L Fischer, Richard E HonkanenAbstract:Fostriecin and cytostatin are structurally related natural inhibitors of serine/threonine phosphatases, with promising antitumor activity. The total synthesis of these antitumor agents has enabled the production of structural analogs, which are useful to explore the biological significance of features contained in the parent compounds. Here, the inhibitory activity of Fostriecin, cytostatin, and 10 key structural analogs were tested in side-by-side phosphatase assays to further characterize their inhibitory activity against PP1c (Ser/Thr protein phosphatase 1 catalytic subunit), PP2Ac (Ser/Thr protein phosphatase 2A catalytic subunit), PP5c (Ser/Thr protein phosphatase 5 catalytic subunit), and chimeras of PP1 (Ser/Thr protein phosphatase 1) and PP5 (Ser/Thr protein phosphatase 5), in which key residues predicted for inhibitor contact with PP2A (Ser/Thr protein phosphatase 2A) were introduced into PP1 and PP5 using site-directed mutagenesis. The data confirm the importance of the C9-phosphate and C11-alcohol for general inhibition and further demonstrate the importance of a predicted C3 interaction with a unique cysteine (Cys269) in the β12–β13 loop of PP2A. The data also indicate that additional features beyond the unsaturated lactone contribute to inhibitory potency and selectivity. Notably, a derivative of Fostriecin lacking the entire lactone subunit demonstrated marked potency and selectivity for PP2A, while having substantially reduced and similar activity against PP1 and PP1/PP2A- PP5/PP2A-chimeras that have greatly increased sensitivity to both Fostriecin and cytostatin. This suggests that other features [e.g., the (Z,Z,E)-triene] also contribute to inhibitory selectivity. When considered together with previous data, these studies suggest that, despite the high structural conservation of the catalytic site in PP1, PP2A and PP5, the development of highly selective catalytic inhibitors should be feasible.
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fundamental role of the Fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition
Journal of the American Chemical Society, 2003Co-Authors: Suzanne B Buck, Kathy Bonness, Richard E Honkanen, Satoshi Ichikawa, C M Gauss, Danielle R Soenen, Mark R Swingle, Christophe Hardouin, Inkyu Hwang, Dale L BogerAbstract:Key derivatives and analogues of Fostriecin were prepared and examined that revealed a fundamental role for the unsaturated lactone and confirmed the essential nature of the phosphate monoester. Thus, an identical 200-fold reduction in protein phosphatase 2A (PP2A) inhibition is observed with either the saturated lactone (7) or with an analogue that lacks the entire lactone (15). This 200-fold increase in PP2A inhibition attributable to the unsaturated lactone potentially may be due to reversible C269 alkylation within the PP beta12-beta13 active site loop accounting for PP2A/4 potency and selectivity.
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Fostriecin chemistry and biology
Current Medicinal Chemistry, 2002Co-Authors: D S Lewy, C M Gauss, Danielle R Soenen, Dale L BogerAbstract:A review of the current status of the chemistry and biology of Fostriecin (CI-920) is provided. Fostriecin is a structurally unique, naturally-occurring phosphate monoester that exhibits potent and efficacious antitumor activity. Initially it was suggested that its activity could be attributed to a direct, albeit weak, inhibition of the enzyme topoisomerase II. However, recent studies have shown that Fostriecin inhibits the mitotic entry checkpoint through the much more potent and selective inhibition of protein phosphatase 2A (PP2A) and protein phosphatase 4 (PP4). In fact, it is the most selective small molecule inhibitor of a protein phosphatase disclosed to date. The contribution, if any, that topoisomerase II versus PP2A/PP4 inhibition makes to Fostriecin's antitumor activity has not yet been fully defined. Initial phase I clinical trials with Fostriecin never reached dose-limiting toxicity or therapeutic dose levels and were halted due to its storage instability and unpredictable chemical purity. Hence, the total synthesis of Fostriecin has been pursued in order to confirm its structure and stereochemistry, to provide access to quantities of the pure natural product, and to access key partial structures or simplified/stable analogs. Several additional natural products have been isolated which contain similar structural features (phospholine, phoslactomycins, phosphazomycin, leustroducsins, sultriecin, and cytostatin), and some exhibit comparable biological properties.
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total synthesis of Fostriecin ci 920
ChemInform, 2001Co-Authors: Dale L Boger, Satoshi Ichikawa, Wenge ZhongAbstract:The first total synthesis of the potent antitumor agent Fostriecin (CI-920) is described, confirming the relative and absolute stereochemistry assignments. Fostriecin is a unique phosphate monoester which exhibits weak topoisomerase II inhibition (IC50 = 40 μM) and more potent and selective protein phosphatase 2A and 4 (PP2A and PP4) inhibition (IC50 = 40−3 nM and 1.5 nM), resulting in mitotic entry checkpoint inhibition. Phase I clinical trials with Fostriecin, which were the first to explore the potential of this novel mechanism of action, were halted even before therapeutic concentrations were reached or dose-limiting toxicity established due to problems of drug stability observed during storage of naturally derived material. The synthesis of Fostriecin detailed herein is the first stage of efforts that may serve to address these limitations to the clinical examination of this or related promising new antitumor agents.
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determination of the relative and absolute stereochemistry of Fostriecin ci 920
Journal of Organic Chemistry, 1997Co-Authors: Dale L Boger, Masataka Hikota, Bryan M LewisAbstract:The absolute stereochemistry of Fostriecin (1, CI-920), a potent antitumor antibiotic presently in Phase I clinical trials at NCI, was determined to be 5R,8R,9R,11R. 2D 1H−1H NMR NOE experiments co...
Masakatsu Shibasaki - One of the best experts on this subject based on the ideXlab platform.
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synthetic strategies of Fostriecin
Heterocycles, 2005Co-Authors: Masakatsu Shibasaki, Motomu KanaiAbstract:Fostriecin is a naturally occurring triene-containing phosphate ester, which exhibits a potent and selective PP2A inhibitory activity. Due to its interesting chemical structure and biological activity, strategically unique total syntheses of Fostriecin were reported from several groups. An overview of the synthesis and chemistry-based structure-activity relationships of Fostriecin is described in this review.
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catalyst controlled asymmetric synthesis of Fostriecin and 8 epi Fostriecin
Journal of the American Chemical Society, 2005Co-Authors: Keisuke Maki, Motomu Kanai, Rie Motoki, Kunihiko Fujii, Takayasu Kobayashi, Shinri Tamura, Masakatsu ShibasakiAbstract:Catalytic asymmetric synthesis of the natural antibiotic Fostriecin (CI-920) and its analogue 8-epi-Fostriecin and evaluation of their biological activity are described. We used four catalytic asymmetric reactions to construct all of the chiral centers of Fostriecin and 8-epi-Fostriecin; cyanosilylation of a ketone, Yamamoto allylation, direct aldol reaction, and Noyori reduction, two of which were developed by our group. Catalytic enantioselective cyanosilylation of ketone 13 produced the chiral tetrasubstituted carbon at C-8. Both enantiomers of the product cyanohydrin were obtained with high enantioselectivity by switching the center metal of the catalyst from titanium to gadolinium. Yamamoto allylation constructed the C-5 chiral carbon in the alpha,beta-unsaturated lactone moiety. A direct catalytic asymmetric aldol reaction of an alkynyl ketone using LLB catalyst constructed the chirality at C-9 with the introduction of a synthetically versatile alkyne moiety, which was later converted to cis-vinyl iodide, the substrate for the subsequent Stille coupling for the triene synthesis. Noyori reduction produced the secondary alcohol at C-11 from the acetylene ketone 6 with excellent selectivity. Importantly, all the stereocenters were constructed under catalyst control in this synthesis. This strategy should be useful for rapid synthesis of stereoisomers of Fostriecin.
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chapter 13 catalytic asymmetric total synthesis of strychnine and Fostriecin
Strategies and Tactics in Organic Synthesis, 2004Co-Authors: Masakatsu Shibasaki, Motomu Kanai, Takashi OhshimaAbstract:This chapter describes the success achieved in catalytic asymmetric total syntheses of (-)-strychnine and Fostriecin. Both of the total syntheses involve catalytic asymmetric carbon–carbon bond forming reactions using bifunctional catalysts developed as key steps. Strychnine is the flagship compound of the family of Strychnos alkaloids and, considering its molecular weight, is one of the most complex natural products. Only twenty-four skeletal atoms are assembled in seven rings and its structure contains six contiguous asymmetric carbon atoms of which five are included within one saturated six-membered ring. Strychnine toxicity arises from the blocking of postsynaptic inhibition in the spinal cord and lower brain stem where it acts as a competitive ligand at the neuronal receptor for glycine. This property has made strychnine useful as a tool in experimental pharmacology. Fostriecin is a novel metabolite of Streptomyces pulveraceus. It displays antitumor activity against a broad range of cancerous cell lines in vitro . This activity is suggested to be intimately related to the potent and well-selective inhibitory activity against serine/threonine phosphatase PP2A. Detailed studies on structure–activity relationship of Fostriecin might lead to a new insight into the selective roles of phosphatase subtypes.
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formal catalytic asymmetric total synthesis of Fostriecin
Organic Letters, 2003Co-Authors: Kunihiko Fujii, Keisuke Maki, Motomu Kanai And, Masakatsu ShibasakiAbstract:The common synthetic intermediate of a potent and promising anticancer agent, Fostriecin, was synthesized using a unique method that combines four catalytic asymmetric reactions as shown above.