- Targeted Covalent Inhibition of Plasmodium FK506 Binding Protein 35
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FK506-binding protein 35, FKBP35, has been implicated as an essential malarial enzyme. Rapamycin and FK506 exhibit antiplasmodium activity in cultured parasites. However, due to the highly conserved nature of the binding pockets of FKBPs and the immunosuppressive properties of these drugs, there is a need for compounds that selectively inhibit FKBP35 and lack the undesired side effects. In contrast to human FKBPs, FKBP35 contains a cysteine, C106, adjacent to the rapamycin binding pocket, providing an opportunity to develop targeted covalent inhibitors of Plasmodium FKBP35. Here, we synthesize inhibitors of FKBP35, show that they directly bind FKBP35 in a model cellular setting, selectively covalently modify C106, and exhibit antiplasmodium activity in blood-stage cultured parasites.
- Atack, Thomas C.,Raymond, Donald D.,Blomquist, Christa A.,Pasaje, Charisse Flerida,McCarren, Patrick R.,Moroco, Jamie,Befekadu, Henock B.,Robinson, Foxy P.,Pal, Debjani,Esherick, Lisl Y.,Ianari, Alessandra,Niles, Jacquin C.,Sellers, William R.
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supporting information
p. 2131 - 2138
(2020/12/17)
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- Challenges in the Development of a Thiol-Based Broad-Spectrum Inhibitor for Metallo-β-Lactamases
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Pathogens, expressing metallo-β-lactamases (MBLs), become resistant against most β-lactam antibiotics. Besides the dragging search for new antibiotics, development of MBL inhibitors would be an alternative weapon against resistant bacterial pathogens. Inhibition of resistance enzymes could restore the antibacterial activity of β-lactams. Various approaches to MBL inhibitors are described; among others, the promising motif of a zinc coordinating thiol moiety is very popular. Nevertheless, since the first report of a thiol-based MBL inhibitor (thiomandelic acid) in 2001, no steps in development of thiol based MBL inhibitors were reported that go beyond clinical isolate testing. In this study, we report on the synthesis and biochemical characterization of thiol-based MBL inhibitors and highlight the challenges behind the development of thiol-based compounds, which exhibit good in vitro activity toward a broad spectrum of MBLs, selectivity against human off-targets, and reasonable activity against clinical isolates.
- Büttner, Dominik,Kramer, Jan S.,Klingler, Franca-M.,Wittmann, Sandra K.,Hartmann, Markus R.,Kurz, Christian G.,Kohnh?user, Daniel,Weizel, Lilia,Brüggerhoff, Astrid,Frank, Denia,Steinhilber, Dieter,Wichelhaus, Thomas A.,Pogoryelov, Denys,Proschak, Ewgenij
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p. 360 - 372
(2017/12/18)
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- Extension of the "ring switch" approach to glutamate antagonists to δ-lactam urethanes
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The versatile "ring switching" approach to antagonists of glutamate receptors has been extended to the use of δ-lactam urethanes. Three different types of δ-lactam urethane aldehydes 17, 26 and 59 have been used successfully in this approach. Altering dia
- Coe, Diane,Drysdale, Martin,Philps, Oliver,West, Robert,Young, Douglas W.
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p. 2459 - 2472
(2007/10/03)
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- Highly enantioselective synthesis of cyclic and functionalized α-amino acids by means of a chiral phase transfer catalyst
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The chiral quaternary ammonium salt 1 serves as phase transfer catalyst for the enantioselective conversion of the glycine derivative 2 to a variety of cyclic and acyclic chiral α amino acids with enantioselectivities as high as 200:1 in alkylation and Michael addition reactions.
- Corey,Noe, Mark C,Xu, Feng
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p. 5347 - 5350
(2007/10/03)
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- Synthetic Route to the "Tricarbonyl" Region of FK-506
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Coupling of a complex lithiodithiane to (S)-tert-butyl N-methoxalylpipecolate leads in three steps to the title substructure.
- Egbertson, Melissa,Danishefsky, Samuel J.
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