Monoaryl- and bisaryldihydroxytropolones as potent inhibitors of inositol monophosphatase

Journal of Medicinal Chemistry

Volumn 40, Issue 26, 1997, Pages 4208-4221

  Piettre, Serge R ^a,b   André, Catherine ^a   Chanal, Marie Christine ^a   Ducep, Jean Bernard ^a   Lesur, Brigitte ^a   Piriou, François ^a   Raboisson, Pierre ^a   Rondeau, Jean Michel ^a   Schelcher, Charles ^a   Zimmermann, Pascale ^a   Ganzhorn, Axel J ^a  

^a SANOFI   (France)

^b UNIVERSITÉ DE ROUEN   (France)

Author keywords

[No Author keywords available]

Indexed keywords

3,7 DIHYDROXYTROPOLONE; BISPHOSPHONIC ACID DERIVATIVE; INOSITOL 1 PHOSPHATASE; INOSITOL 1 PHOSPHATASE INHIBITOR; L 690330; LITHIUM; TROPOLONE DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; BROMINATION; COMPETITIVE INHIBITION; CONCENTRATION RESPONSE; DRUG SYNTHESIS; ENZYME INHIBITOR INTERACTION; METHYLATION; STRUCTURE ACTIVITY RELATION;

BINDING SITES; DIPHOSPHONATES; ENZYME INHIBITORS; ESCHERICHIA COLI; HUMANS; INOSITOL PHOSPHATES; MAGNETIC RESONANCE SPECTROSCOPY; MASS SPECTROMETRY; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PHOSPHORIC MONOESTER HYDROLASES; RECOMBINANT PROTEINS; TROPOLONE;

EID: 6844236354     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9701942     Document Type: Article

References (55)

1. Billington, D. C. The Inositol Phosphates. Chemical Synthesis and Biological Significance; VCH Publisher: Wheinheim, 1991; pp 9-21.
2. (a) Hallcher, L. M.; Sherman, W. R. The Effect of Lithium Ion and Other Agents on the Activity of myo-Inositol Monophosphatase from Bovine Brain. J. Biol. Chem. 1980, 255, 10896-10901.
3. (b) Berridge, M. J.; Downes, P. F.; Hanley, M. R. Lithium Amplifies Agonist-Dependent Phosphatidylinositol Responses in Brain and Salivary Glands. Biochem. J. 1982, 206, 587-595.
4. Nahorski, S. R.; Ragan, C. L; Challiss, R. A. J. Lithium and the Phosphoinositide Cycle: An Example of Uncompetitive Inhibition and its Pharmacological Consequences. Trends Pharmacol Sci. 1991, 12, 297-303.
5. Mitchell, P. B.; Parker, G. B. Treatment of Bipolar Disorders. Med. J. Aust. 1991, 151, 488-493.
6. Peet, M.; Pratt, J. P. Lithium. Current Status in Psychiatric Disorders. Drugs 1993, 46, 7-17.
7. (a) Atack, J. R.; Fletcher, S. R. Inhibitors of Inositol Monophosphatase. Drugs Future 1994,19, 857-866 and references therein (review article).
8. (b) van Steijn, A. M. P.; Willems, H. A. M.; de Boer, Th.; Geurts, J. L. T.; van Boeckel, C. A. A. Synthesis of myo-Inositol-1-Phosphatase Inhibitors in which the Phosphate Group is Replaced by Less Polar Groups. Bioorg. Med. Chem. Lett. 1995, 5, 469-474.
9. Schulz, J.; Wilkie, J.; Lightfoot, Ph.; Rutherford, T.; Gani, D. Synthesis and Properties of Mechanismbased Inhibitors and Probes for Inositol Monophosphatase Derived from 6-O-(2'-Hydroxyethyl)-(1R,2,4,6R)-cyclohexane 1,2,4,6-tetraol. J. Chem. Soc., Chem. Commun. 1995, 2353-2356.
10. Schnetz, N.; Guédat, Ph.; Spiess, B.; Schiewer, G. Synthesis of Thioanalogues of myo-Inositol-1-monophosphate as Possible Inhibitors of myo-Inositol Monophosphatase. Bull. Soc. Chim. Fr. 1996, 133, 205-208.
11. McAllister, G.; Whiting, P.; Hammond, E. A.; Knowles, M. R.; Atack, J. R.; Bailey, F. J.; Maigetter, R.; Ragan, C. I. cDNA Cloning of Human and Rat Brain myo-Inositol Monophosphatase. Biochem. J. 1992, 284, 749-754.
12. (a) Bone, R.; Springer, J. P.; Atack, J. R. Structure of Inositol Monophosphatase, the Putative Target of Lithium Therapy. Proc. Natl Acad. Sci. U.S.A. 1992, 89, 10031-10035.
13. (b) Bone, R.; Frank, L.; Springer, J. P.; Pollack, S. J.; Osborne S.; Atack, J. R.; Knowles, M. R.; McAllister, G.; Ragan, C. I.; Broughton, H. B.; Baker, R.; Fletcher, S. R. Structural Analysis of Inositol Monophosphatase Complexes with Substrates. Biochemistry 1994, 33, 9460-9467.
14. Bone, R.; Frank, L.; Springer, J, P.; Atack, J. R. Structural Studies of Metal Binding by Inositol Monophosphatase: Evidence for two-Metal Ion Catalysis. Biochemistry 1994, 33, 9468-9476.
15. Ganzhorn, A. J.; Rondeau, J.-M. Structure of an Enzyme-Substrate Complex and the Catalytic Mechanism of Human Brain myo-Inositol Monophosphatase. Protein Eng. 1997, 10 (Suppl.), 61.
16. (a) Ganzhorn, A. J.; Chanal, M.-Ch. Kinetic Studies with myoInositol Monophosphatase from Bovine Brain. Biochemistry 1990, 29, 6065-6071.
17. (b) Greasley, P. J.; Gore, M. G. Bovine Inositol Monophosphatase. Studies on the Binding Interactions of Magnesium, Lithium and Phosphate Ions. FEBS Lett. 1993, 331, 114-118.
18. +. Eur. J. Biochem. 1993, 212, 693-704.
19. Pollack, J. S.; Atack, J. R.; Knowles, M. R.; McAllister, G.; Ragan, C. I.; Baker, R.; Fletcher, S. R.; Iversen, L. L.; Broughton, H. B. Mechanism of Inositol Monophosphatase, the putative Target of Lithium Therapy. Proc. Natl. Acad. Sci. U.S.A. 1994, 91, 5766-5770.
20. (e) Wilkie, J.; Cole, A. G.; Gani, D. 3-Dimensional Interactions between Inositol Monophosphatase and its Substrates, Inhibitors and Metal Ion Cofactors. J. Chem. Soc., Perkin Trans. 1 1995, 2709-2727.
21. (f) Ganzhorn, A. J.; Lepage, P.; Pelton, P. D.; Strasser, F.; Vincendon, P.; Rondeau, J.-M. The contribution of Lysine-36 to Catalysis by Human myo-Inositol Monophosphatase. Biochemistry 1996, 35, 10957-10966.
22. (g) Strasser, F.; Pelton, P. D.; Ganzhorn, A. J. Kinetic Characterization of Enzyme Forms Involved in Metal Ion Activation and Inhibition of Myo-inositol Monophosphatase. Biochem. J. 1995, 307, 585-593.
23. (a) Baker, R.; Carrick, C.; Leeson, P. D.; Lennon, I. C.; Liverton, N. J. Design and Synthesis of 6α-Substituted 2β, 4α-Dihydroxy1-phosphoryloxycyclohexanes, Potent Inhibitors of Inositol Monophosphatase. J. Chem. Soc., Chem. Commun. 1991, 298-300.
24. (b) Fletcher, S. R.; Baker, R.; Ladduwhahetty, T.; Sharpe, A,; Teall, M.; Atack, J. R. 4-Hydroxyphenoxymethylene Bisphosphonic Acid Derivatives: Potent, Non-hydrolysable Inhibitors of myo-Inositol Monophosphatase. Bioorg. Med. Chem. Lett. 1993, 3, 141-146.
25. (a) Atack, J. R.; Cook, S. M.; Watt, A. P.; Fletcher, S. R.; Ragan, C. I. In Vitro and In Vivo Inhibition of Inositol Monophosphatase by the Bisphosphonate L-690, 330. J. Neurochem. 1993, 60, 652-658.
26. (b) Atack, J. R.; Prior, A. M.; Fletcher, S. R.; Quirk, K; McKernan, R.; Ragan, C. I. Effects of L-690, 488, a Prodrug of the Bisphosphonate Inositol Monophosphatase Inhibitor L-690, 330, on Phosphatidylinositol Markers. J. Pharmacol. Exp. Ther. 1994, 270, 70-76.
27. Piettre, S. R.; Ganzhorn, A.; Hoflack, J.; Islam, K.; Hornsperger, J.-M. α-Hydroxytropolones: A New Class of Potent Inhibitors of Inositol Monophosphatase and Other Bimetallic Enzymes. J. Am. Chem. Soc. 1997, 119, 3201-3204.
28. 15
29. 14 see Experimental Section.
30. Haworth, R. D.; Hobson, J. D. Purpurogallin. Part IV. Some Properties of Tropolones. J. Chem. Soc. 1951, 561-568.
31. Pietra, F. Revival of Troponoid Chemistry. Acc. Chem. Res 1979, 12, 132-138.
32. Suri, S. C.; Nair, V. Palladium(0)-Catalysed Reaction of 2-Bromo-7-methoxytropone with Arylboronic Acids: An Efficient Synthesis of 2-Aryl-7-methoxytropones. Synthesis 1990, 695-696.
33. (a) Takeshita, H.; Mon, A.; Kusaba, T. An Improved Synthesis of 2,7-Dihydroxytropone (3-Hydroxytropolone). Synthesis 1986, 578-579.
34. (b) Takeshita, H.; Mori, A.; Kusaba, T.; Watanabe, H. Preparation of Polyacetoxytropones and Polyhydroxytropolones by Acetolysis and Hydrolysis of Halotroponoids by Acetyl Trifluoroacetate with Exhaustive Displacement of Halogens on the Tropone Ring. Predominant Formation of Reductive Acetolysates from Fully-Substituted Tropones. Bull. Chem. Soc. Jpn. 1987, 60, 4325-4333.
35. Nozoe, T. Recent Advances in the Chemistry of Troponoids and Related Compounds in Japan, PureAppl. Chem. 1971, 28, 239-280.
36. Preparation of boronic acids was needed in several cases.
37. 18
38. (a) Davis, A. L.; Keeler, J.; Lane, E.; Moskau, D. Experiments for Recording Pure Absorption Heteronuclear Correlation Spectra Using Pulsed Field Gradients. J. Magn. Res. 1992, 98, 207-216.
39. 13C Assignments from Sensitivity-Enhanced Detection of Heteronuclear Multiple-Bond Connectivity by 2-D Multiple Quantum NMR. J. Am. Chem. Soc. 1986, 108, 2093-2094.
40. These included treatment with tert-butyllithium, tributyltin hydride, and tris(trimethylsilyl)silane.
41. The two experiments were carried out by the same person using the same experimental procedure; the results thus demonstrate, in this precise case, the extreme sensitivity of the reaction to minute variations in experimental conditions. This is the only example of ring contraction observed in this study; it is of note that it is also the only example of a reaction between isomer 16 and a boronic acid substituted in the para position by an electron-withdrawing substituent. The results may be indicative of an activation of the tropolone ring by thep-(trifluoromethyl)-phenyl group toward nucleophilic species.
42. The direct introduction of a nucleophile on the tropolone ring resulted in the substitution of a methoxy substituent, leaving the bromine untouched; S. R. Piettre, C. Scheicher, unpublished results.
43. Treatment of permethylated dihydroxytropolones with TMSI at room temperature resulted in the rapid cleavage of two of the three ether functions; removal of the third methoxy group was much slower (20% unconsumed after 24 h at room temperature) and required heating.
44. 1H NMR spectroscopy.
45. 1H NMR spectroscopy); however, this material was highly impure, and efforts to purify it did not succeed. The methods used to attempt purification include classical chromatography or HPLC on silica gel (reverse-phase), cellulose, and resins as well as crystallization in various solvents.
46. Horner, L.; Göwecke, S. o- Quinones. XVI. Addition Reactions of 3-Methoxy-o-quinone. Chem. Ber. 1961, 94, 1267-1276.
47. Commercially available purpurogallin was sublimed (200 °C/ 0.001 mbar) before use.
48. Nozoe, T.; Doi, K.; Hashimoto, T. Synthesis of Puberulonic Acid. Bull. Chem. Soc. Jpn. 1960, 33, 1071-1074.
49. Cleland, W. W. Statistical Analysis of Enzyme Kinetic Data. In Methods in Enzymology; Purich, D. L., Ed.; Academic Press: New York, 1979; Vol. 63, pp 103-138.
50. Only 10 compounds encompassing the 3,7-dihydroxytropolonic unit have been reported so far in the literature, among which are the parent compound 8, 3,5,7-trihydroxytropolone, and the natural products puberulom'c acid and puberulic acid.
51. It should be noted that the results described in this paper are adaptable to solid-phase synthesis; Piettre, S. R.; Baltzer, S. A New Approach to the Solid-Phase Suzuki Reaction. Tetrahedron Lett. 1997, 38, 1197-2000.
52. Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatographie Technique for Preparative Separation with Moderate Resolution. J. Org. Chem. 1978, 43, 2923-2924.
53. The boronic acid and ethanol can also be added sequentially (cases of poor solubility).
54. +-sensitive Enzymes ans Proceeds via Inositol 4-Phosphate. Biochem. J. 1988, 249, 143-148.
55. Modeling experiments were carried out as described in ref 11.