Total synthesis of the 5-methylenephosphonate analogue of D-myo-inositol 1,4,5-trisphosphate

Falck, John R.; Abdali, Abdelkrim; Wittenberger, Steven J.

doi:10.1039/c39900000953

Cited by 35 publications

(5 citation statements)

References 8 publications

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“…Allylic Bromide 15. Powdered Na 2 CO 3 (1.07 g, 10.1 mmol) was added to a solution of phenylselenyl bromide (1.72 g, 7.31 mmol) in CH 2 Cl 2 (20 mL) . The mixture was cooled to −78 °C, and a solution of exocyclic alkene 14 (2.81 g, 7.23 mmol) in CH 2 Cl 2 (20 mL) added via cannula under Ar.…”

Section: Methodsmentioning

confidence: 99%

Cyclohexenyl and Cyclohexylidene Inhibitors of 3-Dehydroquinate Synthase: Active Site Interactions Relevant to Enzyme Mechanism and Inhibitor Design

Montchamp

Frost

1997

J. Am. Chem. Soc.

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Cyclohexenyl and cyclohexylidene inhibitors possessing strategically placed olefinic residues, in general, bind to 3-dehydroquinate (DHQ) synthase more tightly than similarly substituted cyclohexyl inhibitors. All of the newly synthesized inhibitors were prepared from a common DHQ derivative. Cyclohexenyl phosphate 1 is the most potent inhibitor of DHQ synthase thus far identified with an inhibition constant (K i = 1.2 × 10-10 M), indicating active site binding 1000-fold tighter relative to the corresponding cyclohexyl phosphate 5. Cyclohexenyl tricarboxylate 2 binds 700-fold more tightly than similarly substituted cyclohexyl tricarboxylate 6 and is the first example of a nanomolar-level inhibitor (K i = 8.6 × 10-9 M) possessing neither a phosphate monoester nor a phosphonic acid. Cyclohexenyl homophosphonate 4 (K i = 3.0 × 10-8 M) and cyclohexylidene homophosphonate 10 (K i = 3.2 × 10-9 M) bind 57- and 530-fold, respectively, more tightly than the corresponding cyclohexyl homophosphonate 8. Cyclohexylidene homophosphonate 10 is the first example of a nanomolar-level, homophosphonic acid inhibitor of DHQ synthase. Cyclohexylidene phosphonate 9 (K i = 2.9 × 10-10 M) is a 2.9-fold more potent inhibitor relative to cyclohexyl phosphonate 7 which was previously the most potent, slowly-reversible inhibitor of DHQ synthase. Cyclohexenyl phosphonate 3 (K i = 1.2 × 10-9 M) is the only olefin-containing, carbocyclic inhibitor where improved binding over the corresponding cyclohexyl analogue was not observed. The impact of olefinic residues in inhibitors on active site binding may indicate that DHQ synthase plays an active catalytic role during E1cb elimination of inorganic phosphate from enzyme-bound substrate.

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Section: Methodsmentioning

confidence: 99%

Cyclohexenyl and Cyclohexylidene Inhibitors of 3-Dehydroquinate Synthase: Active Site Interactions Relevant to Enzyme Mechanism and Inhibitor Design

Montchamp

Frost

1997

J. Am. Chem. Soc.

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“…31P NMR (D20,36 MHz): 547.74(lP,d,J=10.1Hz,5-P), 46.55 (2 P, d, J = 10.1 Hz, 1-P, 3-P). MS: m/z (-ve ion FAB) 466 [100, ( -)-], 432 (15), 238 (15), 113 (17), 95 [(PS02)-, 40]. MS: m/z 466.886 ( -H)-(caled for CsHuOigPgSg, 466.886).…”

Section: Methodsmentioning

confidence: 99%

Synthesis of Selective Non-Ca2+ Mobilizing Inhibitors of D-myo-Inositol 1,4,5-Trisphosphate 5-Phosphatase

Lampe¹,

Liu²,

Potter³

1994

J. Med. Chem.

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Syntheses of novel phosphorothioate-based non-Ca(2+)-releasing inhibitors of myo-inositol 1,4,5-trisphosphate 5-phosphatase are described. 1L-myo-Inositol 1,4,5-trisphosphorothioate, myo-inositol 1,3,5-trisphosphorothioate, and 1L-chiro-inositol 1,4,6-trisphosphorothioate have been synthesized from 1L-2,3,6-tri-O-benzyl-1-O-(cis-prop-1-enyl)-myo-inositol, 2,4,6-tris-O-(p-methoxybenzyl)-myo-inositol orthoformate and 1L-2,3,5-tri-O-benzyl-chiro-inositol, respectively. 1L-2,3,5-Tri-O-benzyl-chiro-inositol was also used to prepare 1L-chiro-inositol 1,4,6-trisphosphate. The phosphorothioates did not mobilize intracellular Ca2+ but were highly potent inhibitors of Ins(1,4,5)P3 5-phosphatase, and myo-inositol 1,3,5-trisphosphorothioate and 1L-chiro-inositol 1,4,6-trisphosphorothioate were selective for this enzyme.

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“…The dichloromethane solution was washed with 10% sodium metabisulfite (3 x 20 cm3), sodium hydrogen carbonate solution (20 cm3) and brine (20 cm3), dried (MgSO,), filtered and the dichloromethane was evaporated to give an oil. The oily residue was chromatographed on silica gel (ether-pentane, 3: 1) to give the title compound; yield (55 mg, 84%); R, = 0.20 (ethyl acetate); 6,(CDCl,; 300 MHz) 2.63-2.83 (8 H, m, OCH2CH2CN), 3.55 (1 H, dd, J9.9,1.7,3-H), 3.74-4.98 (19 H, m, 5 Ins C-H, 3 CH2C6Hs and 4 OCH2CH,CN) and and -2.99; m / z FAB' 823 [(M + H)+, c 1x1, 728 (13), 581 (15), 328 (29), 147 (53) and 107 (100). (1.55 g, 3.16 mmol) and DABCO (71 mg, 0.65 mmol) in a mixture of ethanol-toluene-water (7: 3: 1, v/v/v) was heated.…”

Section: 6-tri-o-benzyl-45-bis[bis(2-cyanoethoxy)phospho]-1 -0-p-rnet...mentioning

confidence: 99%

Total synthesis of the second messenger analogue D-myo-inositol 1-phosphorothioate 4,5-bisphosphate: optical resolution of DL-1-O-allyl-2,3,6-tri-O-benzyl-myo-inositol and fluorescent labelling of myo-inositol 1,4,5-trisphosphate

Lampe¹,

Mills²,

Potter³

1992

J. Chem. Soc., Perkin Trans. 1

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Total synthesis of the 5-methylenephosphonate analogue of D-myo-inositol 1,4,5-trisphosphate

Abstract: The 5-methylenephosphonate analogue of D-myo-inositol 1,4,5-trisphosphate has been prepared from (-)-quinic acid and shown to be a long-lived agonist of calcium mobilization.

Cited by 35 publications

References 8 publications

Cyclohexenyl and Cyclohexylidene Inhibitors of 3-Dehydroquinate Synthase: Active Site Interactions Relevant to Enzyme Mechanism and Inhibitor Design

Cyclohexenyl and Cyclohexylidene Inhibitors of 3-Dehydroquinate Synthase: Active Site Interactions Relevant to Enzyme Mechanism and Inhibitor Design

Synthesis of Selective Non-Ca2+ Mobilizing Inhibitors of D-myo-Inositol 1,4,5-Trisphosphate 5-Phosphatase

Total synthesis of the second messenger analogue D-myo-inositol 1-phosphorothioate 4,5-bisphosphate: optical resolution of DL-1-O-allyl-2,3,6-tri-O-benzyl-myo-inositol and fluorescent labelling of myo-inositol 1,4,5-trisphosphate

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