412
M. Fonvielle et al. / Bioorg. Med. Chem. Lett. 17 (2007) 410–413
19. (a) Dreyer, M. K.; Schulz, G. E. J. Mol. Biol. 1996, 259,
458; (b) Fessner, W.-D.; Schneider, A.; Held, H.; Sinerius,
G.; Walter, C.; Hixon, M.; Scloss, J. V. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2219; (c) Marks, G. T.; Harris, T. K.;
Massiah, M. A.; Mildvan, A. S.; Harrison, D. H. T.
Biochemistry 2001, 40, 6805.
In conclusion, we have devised the synthesis and evalu-
ation of new competitive inhibitors of mammalian cyto-
solic glycerophosphate dehydrogenase. These products
(or their prodrug derivatives) may have applications as
anti-obesity drugs. One of these compounds, phospho-
nopropionohydroxamate 3, is of special interest for the
following reasons:
20. Fonvielle, M.; Weber, P.; Dabkowska, K.; Therisod, M.
Bioorg. Med. Chem. Lett. 2004, 14, 2923.
21. Fonvielle, M.; Mariano, S.; Therisod, M. Bioorg. Med.
Chem. Lett. 2005, 75, 2906.
— Being a phosphonate, it is insensitive to hydrolysis
by phosphatases.
— It does not interfere with other enzymes of the gly-
colysis, namely FBP-aldolase and triosephosphate
isomerase, for which it is an only very poor
inhibitor.
22. (a) Brown, H. C.; McDaniel, D. H.; Hafloger, O. In
Determination of Organic Structures by Physical Methods;
Braude, E. A., Nachod, F. C., Eds.; Academic Press: New
York, 1955; p 567; (b) McElroy, W. D.; Glass, B. In
Phosphorous Metabolism; Johns Hopkins University Press:
Baltimore, 1951; vol. 1, (c) Freedman, L. D.; Doak, G. O.
Chem. Rev. 1957, 57, 479.
Compounds 3 and 4 could also be of interest for further
studies of the catalytic mechanism of GPDH based on
structural analyses (the crystal structure of the human
enzyme was reported recently.)27
23. Weber, P.; Fonvielle, M.; Therisod, M. Tetrahedron Lett.
2003, 44, 9047.
24. Synthesis of 4: 47 mmol of triethyl phosphite were added
dropwise to a solution of ethylmalonyl chloride in
diethylether at 0 °C. After 72 h at room temperature, the
excess of triethyl phosphite was evaporated, and the
product (for a large part in enol form, as deduced from its
1H NMR spectrum) distilled (97 °C/0.17 mm). It was then
treated by 1.5 M equivalent of pyridine–borane in pres-
ence of HCl. After neutralization and evaporation of the
mixture, the protected hydroxyphosphonate 4a was dis-
solved in dichloromethane, washed with water, and
purified by flash chromatography (AcOEt/MeOH/H2O,
90:10:1). The final product was obtained after deprotec-
tion with pure TMS–Br (2 h, rt), evaporation, and
treatment with an excess of aqueous hydroxylamine.
Compound 4 was purified by crystallization of the bis-
cyclohexylammonium salt in methanol/AcOEt.
Compound 4a: 1H NMR (CdCl3): d 1.24 (9H, m); 2.66
(2H, m); 4.12 (6H, m); 4.36 (1H, m); 6.72 (1H, br s).
13C NMR (CdCl3, BB): d 13.6; 15.9; 36.4; 62.4; 62.8; 60.5;
60.7; 65; 65.1; 170.3.
Supplementary data
Supplementary data associated with this article can be
References and notes
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31P NMR (CdCl3, BB): d 24.4.
ESI HR-MS: 277.0818 g/mol (M+Na); Th: 277.0811 g/
mol.
Compound 4: 1HNMR (D2O): d 0.75–1.05 (10H, m); 1.25–
1.64 (10H, m); 2 (1H, ddd; 15, 12, 8 Hz); 2.2 (1H, ddd; 15,
4, 3 Hz); 2.79 (2H, m); 3.6 (3H, ddd; 12, 8, 3 Hz).
13C NMR (D2O, BB): d 23.6; 24.3; 29.9; 36.5; 50.1; 65.9;
67.6; 171.
31P NMR (D2O, BB): d 15.8.
ESI HR-MS: 184.0009 g/mol (M+1); Th: 184.0005 g/mol.
25. Synthesis of 5: the intermediate triethyl ester 4a was
mesylated by a standard method (MsCl/NEt3 in reflux-
ing dichloromethane) and treated by another equivalent
of NEt3 to eliminate the OMs group. Michael addition
of benzylamine was performed using 2 equiv of base in
refluxing ethanol, overnight, followed by flash chroma-
tography (pentane/AcOEt, 3:7). The amine was deben-
zylated by hydrogenolysis (Pd/C, 2 atm) in ethanol to
give 5 a. Deprotection of the phosphate, hydroxylamin-
olysis of the ester and isolation of 5 as the cyclohexy-
lammonium salt were performed as for 4.
Compound 5a: 1HNMR (D2O): d 1.28 (3H, t, 7 Hz);
1.35 (6H, t, 7 Hz); 2 (2H, br s); 2.49 (1H, ddd; 16, 11,
8 Hz); 2.8 (1H, ddd; 16, 8, 3 Hz); 3.17 (1H, ddd; 16, 11,
3 Hz); 3.68 (6H, q, 7 Hz).
13C NMR (D2O, BB): d 14; 16.3; 16.4; 36.8; 44.3; 46.7;
60.7; 62.2; 62.3; 62.4; 170.9; 171.2.
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ESI HR-MS: 276.0975 g/mol (M+Na); Th: 276.0971 g/
mol.
Compound 5: 1H NMR (D2O): d 0.89–1.71 (10H, m);