Synthesis and evaluation of two new inhibitors of EPSP synthase

Pansegrau, Paul D.; Anderson, Karen S.; Widlanski, Theodore S.; Ream, Joel E.; Sammons, R. Douglas; Sikorski, James A.; Knowles, Jeremy R.

doi:10.1016/s0040-4039(00)78792-2

Cited by 34 publications

(20 citation statements)

References 14 publications

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“…The triazole moiety in 4−5 was introduced by a copper(I)-catalyzed 1,3-dipolar cycloaddition between azide 14 and 3-phenyl-1-propyne or 3-phenoxy-1-propyne, respectively (Scheme 3). Azide 14 23 was prepared in four steps from protected methyl shikimate 11 24 following a modified procedure. First, treatment of alcohol 11 with mesyl chloride in the presence of trimethylamine and subsequent acid hydrolysis of the acetal gave mesylate 12.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…The combined organic extracts were washed with saturated NaHCO 3 , dried (anhyd Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography, eluting with (60:40) ethyl acetate/hexane, to give the azide 14 (23.5 mg, 85%), as a white solid; mp 102.8–103.0 °C; [α] D 20 = −167.0° ( c 1.1, CHCl 3 ). 1 H NMR (250 MHz, CDCl 3 ) δ: 6.88 (m, 1H, H2), 4.44 (t, J = 4.2 Hz, 1H, H3), 3.86 (m, 1H, H5), 3.77 (s, 3H, OCH 3 ), 3.70 (dd, J = 4.3 and 9.3 Hz, 1H, H4), 2.92 (dd, J = 5.4 and 17.9 Hz, 1H, H6 ax ) and 2.33–2.21 (m, 1H, H6 eq ) ppm.…”

Section: Methodsmentioning

confidence: 99%

“…The combined organic extracts were washed with saturated NaHCO 3 , dried (anhyd Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography, eluting with (60:40) ethyl acetate/hexane, to give the azide 14 23 Methyl (3R,4S,5R)-5-(4-Benzyl-1H-1,2,3-triazol-1-yl)-3,4-dihydroxycyclohex-1-ene-1-carboxylate (15). To a suspension of azide 14 (100 mg, 0.47 mmol) and 3-phenyl-1-propine (0.06 mL, 0.47 mmol) in a 1:1 mixture of t-BuOH-water (1.5 mL), freshly prepared aqueous sodium ascorbate solution (0.47 mL, 1.0 M), followed by aqueous copper(II) sulfate solution (1.5 mL, 0.32 M), were added.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the Enzyme

et al. 2016

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The large conformational changes observed by Molecular Dynamics simulation studies on the product release in the LID and shikimic acid binding (SB) domains of the shikimate kinase (SK) enzyme have been exploited in the development of reversible competitive inhibitors against SK from Mycobacterium tuberculosis and Helicobacter pylori. This enzyme is a recognized target for antibiotic drug discovery. The reported C5-substituted shikimic acid analogues interact with the dynamic apolar pocket that surrounds the C4 and C5 hydroxyl groups of the natural substrate, cause the opening of the LID and SB domains, and capture the essential arginine far from the ATP binding site as required for catalysis. The 3-nitrobenzyl 3e and 5-benzothiophenyl derivatives 3i proved to be the most potent inhibitors. An ester prodrug of 3i was the most efficient derivative in achieving good in vitro activity against H. pylori, having a MIC value of 4 μg/mL.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

“…The combined organic extracts were washed with saturated NaHCO 3 , dried (anhyd Na 2 SO 4 ), filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography, eluting with (60:40) ethyl acetate/hexane, to give the azide 14 23 Methyl (3R,4S,5R)-5-(4-Benzyl-1H-1,2,3-triazol-1-yl)-3,4-dihydroxycyclohex-1-ene-1-carboxylate (15). To a suspension of azide 14 (100 mg, 0.47 mmol) and 3-phenyl-1-propine (0.06 mL, 0.47 mmol) in a 1:1 mixture of t-BuOH-water (1.5 mL), freshly prepared aqueous sodium ascorbate solution (0.47 mL, 1.0 M), followed by aqueous copper(II) sulfate solution (1.5 mL, 0.32 M), were added.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the Enzyme

et al. 2016

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“…The rate of exchange in the presence of dideoxy S3P or C5 deoxy S3P was approximately 800 times slower than the rate of formation of the tetrahedral intermediate from S3P [92,93]. The rate of exchange in the presence of dideoxy S3P or C5 deoxy S3P was approximately 800 times slower than the rate of formation of the tetrahedral intermediate from S3P [92,93].…”

Section: The Catalytic Mechanismmentioning

confidence: 92%

The Inhibition of 5-enolpyruvylshikimate-3-phosphate Synthase as a Model for Development of Novel Antimicrobials

Marques¹,

Pereira²,

Oliveira³

et al. 2007

CDT

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EPSP synthase (EPSPS) is an essential enzyme in the shikimate pathway, transferring the enolpyruvyl group of phosphoenolpyruvate to shikimate-3-phosphate to form 5-enolpyruvyl-3-shikimate phosphate and inorganic phosphate. This enzyme is composed of two domains, which are formed by three copies of ß ß ßß-folding units; in between there are two crossover chain segments hinging the nearly topologically symmetrical domains together and allowing conformational changes necessary for substrate conversion. The reaction is ordered with shikimate-3-phosphate binding first, followed by phosphoenolpyruvate, and then by the subsequent release of phosphate and EPSP. N-[phosphomethyl]glycine (glyphosate) is the commercial inhibitor of this enzyme. Apparently, the binding of shikimate-3-phosphate is necessary for glyphosate binding, since it induces the closure of the two domains to form the active site in the interdomain cleft. However, it is somehow controversial whether binding of shikimate-3-phosphate alone is enough to induce the complete conversion to the closed state. The phosphoenolpyruvate binding site seems to be located mainly on the C-terminal domain, while the binding site of shikimate-3-phosphate is located primarily in the N-terminal domain residues. However, recent results demonstrate that the active site of the enzyme undergoes structural changes upon inhibitor binding on a scale that cannot be predicted by conventional computational methods. Studies of molecular docking based on the interaction of known EPSPS structures with (R)-phosphonate TI analogue reveal that more experimental data on the structure and dynamics of various EPSPS-ligand complexes are needed to more effectively apply structure-based drug design of this enzyme in the future.

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“…Chorismate mutase [E.C. 5.4.99.51 catalyses the Claisen-like rearrangement of chorismate (1 8) to prephenate (19), transferring the phosphoenolpyruvate-derived sidechain so that it becomes directly bonded to the carbocycle. The enzyme activity is found in nature in both monofunctional and bifunctional proteins.…”

Section: Chorismate Mutasementioning

confidence: 99%

The biosynthesis of shikimate metabolites

Dewick¹

1993

Nat. Prod. Rep.

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Synthesis and evaluation of two new inhibitors of EPSP synthase

Cited by 34 publications

References 14 publications

Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the Enzyme

Targeting the Motion of Shikimate Kinase: Development of Competitive Inhibitors that Stabilize an Inactive Open Conformation of the Enzyme

The Inhibition of 5-enolpyruvylshikimate-3-phosphate Synthase as a Model for Development of Novel Antimicrobials

The biosynthesis of shikimate metabolites

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