Synthesis of 3-alkyl-6-phenyl-4(3H)-pteridinones and their 8-oxides. Potential substrates of xanthine oxidase
J. W. G. De Meester
Department of Organic Chemistry, Wageningen Agricultural University, De Dreyen 5, 6703 BC Wageningen, The Netherlands
Search for more papers by this authorW. Kraus
Department of Organic Chemistry, Wageningen Agricultural University, De Dreyen 5, 6703 BC Wageningen, The Netherlands
Search for more papers by this authorH. C. Van Der Plas
Department of Organic Chemistry, Wageningen Agricultural University, De Dreyen 5, 6703 BC Wageningen, The Netherlands
Search for more papers by this authorH. J. Brons
Department of Microbiology, Wageningen Agricultural University, Hesselink van Suchtelenweg 4 6703 CT Wageningen, The Netherlands
Search for more papers by this authorW. J. Middelhoven
Department of Microbiology, Wageningen Agricultural University, Hesselink van Suchtelenweg 4 6703 CT Wageningen, The Netherlands
Search for more papers by this authorJ. W. G. De Meester
Department of Organic Chemistry, Wageningen Agricultural University, De Dreyen 5, 6703 BC Wageningen, The Netherlands
Search for more papers by this authorW. Kraus
Department of Organic Chemistry, Wageningen Agricultural University, De Dreyen 5, 6703 BC Wageningen, The Netherlands
Search for more papers by this authorH. C. Van Der Plas
Department of Organic Chemistry, Wageningen Agricultural University, De Dreyen 5, 6703 BC Wageningen, The Netherlands
Search for more papers by this authorH. J. Brons
Department of Microbiology, Wageningen Agricultural University, Hesselink van Suchtelenweg 4 6703 CT Wageningen, The Netherlands
Search for more papers by this authorW. J. Middelhoven
Department of Microbiology, Wageningen Agricultural University, Hesselink van Suchtelenweg 4 6703 CT Wageningen, The Netherlands
Search for more papers by this authorAbstract
Synthetic routes for the preparation of 3-alkyl-6-phenyl-4(3H)-pteridinones 6 and their corresponding 8-oxides 5 (R = CH3, C2H5, (CH2)2CH3, (CH2)3CH3, CH(CH3)C2H5, CH(CH3)2 and CH(C2H5)CH2OCH(OC2H5)2 are described and their reactivities towards xanthine oxidase from Arthrobacter M-4 are determined. Only the 3-methyl derivative of 6-phenyl-4(3H)-pteridinone and its 8-oxide i. e. 6a and 5a are found to be substrates although their reactivities are still very low. Oxidation takes place at C-2 of the pteridinone nucleus. All the 3-alkyl derivatives are less tightly bound to the enzyme than 6-phenyl-4(3H)-pteridinone. Introduction of the N-oxide at N-8 considerably lowers the binding of the substrates. Inhibition studies have revealed that 3-methyl-6-phenyl-4(3H)-pteridinone (6a) is a non-competitive inhibitor with a Ki-value of 47 μM and the 3-ethyl derivative (6b) an uncompetitive one with a Ki-value of 19.6 μM.
References and Notes
- 2a J. Tramper, A. Nagel and H. C. van der Plas, Rec. Trav. Chim., 98, 224 (1979) b J. Tramper, W. E. Hennink and H. C. van der Plas, J. Appl. Biochem., 4, 263 (1982) c H. C. van der Plas, “ Lectures Heterocyclic Chemistry”, Vol 6, R. N. Castle and T. Kappe, eds, Heterocorporation, P. O. Box 1600 MH, Tampa, FL, 33687 1982, p 1; Supplementary Issue, J. Heterocyclic Chem., 19, S-1 (1982) d J. Tramper, A. van der Kaaden, H. C. van der Plas and W. J. Middelhoven, Biotechn. Letters, 1, 397 (1979).
- 3 J. W. G. De Meester, W. Kraus, W. J. Middelhoven and H. C. van der Plas, “Bio-organic Heterocycles 1986: Synthesis, Mechanisms and Bioactivity (Studies Organic Chemistry 27), Proc. Fourth FECHEM Conference Heterocycles in Bio-Organic Chemistry”, H. C. van der Plas, M. Simonyi, F. C. Alderweireldt, and J. A. Lepoivre, eds, Elsevier, Amsterdam, 1986, p 243.
- 4 J. W. G. De Meester, H. C. van der Plas and W. J. Middelhoven, J. Heterocyclic Chem., submitted for publication (1987).
- 5 H. S. D. Naeff, H. C. van der Plas, J. Tramper and F. Miller, Quant. Struct.-Act. Relat., 4, 161 (1985).
- 6a B. R. Baker and W. F. Wood, J. Med. Chem., 10, 1101 (1967) b B. R. Baker and W. F. Wood, J. Med. Chem., 11, 644 (1968); c B. R. Baker, W. F. Wood and J. A. Kozma, J. Med. Chem., 11, 661 (1968) and references cited herein; d F. Bergmann, L. Levene, H. Goivrin and A. Frank, Biochem. Biophys. Acta, 480, 39, (1977) e R. K. Robins, G. R. Revankar, D. E. O'Brien, R. H. Springer, T. Novinson, A. Albert, K. Senga, J. P. Miller and D. C. Streeter, J. Heterocyclic Chem., 22, 601, (1985).
- 7a F. Bergmann and S. Dickstein, J. Biol. Chem., 765 (1956) b S. Dickstein, F. Bergmann and Y. Henis, J. Biol. Chem., 224, 67, (1957); c F. Bergmann, H. Kwietny, G. Levin and D. J. Brown, J. Am. Chem. Soc., 82, 598 (1960); d T. A. Krenitsky, S. M. Neil, G. B. Elion and G. H. Hitchings, Arch. Biochem. Biophys., 150, 585 (1972) e F. Bergmann and L. Levene, Biochim. Biophys. Acta, 429, 672 (1976); f C. A. Woolfolk and J. S. Downard, J. Bacteriol, 130, 1175 (1977); g C. A. Woolfolk and J. S. Downard, J. Bacteriol., 135, 422 (1978).
- 8a F. Bergmann, L. Levene and I. Tamir, “ Chemistry and Biology of Pteridines”, Proc. Fifth Int. Symp., Konstanz, West Germany, April 14–18, 1975, W. Pfleiderer, ed, Walter de Gruyter, Berlin - New York, 1975, p 603; b F. Bergmann, L. Levene, I. Tamir and R. Rahat, Biochim. Biophys. Acta 480, 21 (1977).
- 9a G. B. Brown, M. A. Stevens and H. W. Smith, J. Biol. Chem., 233, 1513 (1958); b D. Dunn, M. H. Maguire, G. B. Brown and A. Myles, J. Biol. Chem., 244, 4072 (1969); c F. Bergmann and L. Levene, Biochim. Biophys. Acta, 481, 359 (1977).
- 10a E. C. Taylor and K. Lenard, J. Am. Chem. Soc., 90, 2424 (1968); b E. C. Taylor, K. L. Perlman, I. P. Sword, M. Séquin-Frey and P. A. Jacobi, J. Am. Chem. Soc., 95, 6407 (1973).
- 11 B. R. Baker, M. V. Querry, A. F. Kadish and J. H. Williams, J. Org. Chem., 17, 35 (1952).
- 12 E. C. Taylor, K. L. Perlman, Y.-H. Kim, I. P. Sword and P. A. Jacobi, J. Am. Chem. Soc., 95, 6413 (1973).
- 13 Using the above mentioned procedure and starting from 3a and 3f, the compounds 4a and 4f were obtained in an overall yield of 68% and 57% respectively.
- 14a E. Felder, D. Pitré and S. Boveri, J. Med. Chem., 15, 210 (1972); b A. Albert, D. J. Brown and G. Cheeseman, J. Chem. Soc., 474 (1951).
- 15a A. Albert and K. Ohta, J. Chem. Soc. (C), 3727 (1971) b A. Albert, J. Chem. Soc., Perkin Trans I, 1574 (1979).
- 16 W. Kraus, J. W. G. De Meester, H. C. van der Plas and A. van Veldhuizen, Magn. Reson. Chem., submitted for publication.
- 17a
K. Tori,
M. Ogata and
H. Kano,
Chem. Pharm. Bull.,
11,
681
(1963);
b
P. Hamm and
W. van Philipsborn,
Helv. Chim. Acta,
54,
2363
(1971);
c
S. Okada,
A. Hasasayama,
T. Konno and
F. Uchimasu,
Chem. Pharm. Bull.,
19,
344
(1971);
10.1248/cpb.19.1344 Google Scholard S. N. Bannore, J. L. Bose, A. A. Thakar and M. S. Wadia, Indian J. Chem., 13, 609 (1975); e A. Ohta, Y. Akita and Ch. Takagai, Heterocycles, 6, 1881 (1977).
- 18a E. C. Taylor and T. Kobayashi, J. Org. Chem., 38, 2817 (1973); b O. W. Lever, Jr. and B. R. Vestal, J. Heterocyclic Chem., 22, 5 (1985).
- 19a U. Ewers, H. Günther and L. Jaenicke, Chem. Ber., 107, 3275 (1974); b H. Günther and A. Gronenborn, Heterocycles, 11, 337 (1978); c M. Matsuo, S. Matsumoto, T. Kurihara, Y. Akita, T. Watanabe and A. Ohta, Org. Magn. Reson., 13, 172 (1980).
- 20 H. J. Brons, M. Breedveld, W. J. Middelhoven, J. W. G. De Meester, H. C. van der Plas and F. Müller, Biotechn. Appl. Biochem., accepted for publication (1987).
- 21a
W. Pfleiderer and
W. Hutzenlaub,
Angew. Chem.,
7,
1136
(1965);
10.1002/ange.19650772407 Google Scholarb W. Pleiderer and W. Hutzenlaub, Chem. Ber., 106, 3149 (1973); c W. Pfleiderer, Khim. Geterosikl. Soedin., 1299 (1974), through English translation: J. Heterocyclic Compd., 1127 (1974).
- 22 Also at pH = 7.2 a very slow oxidation of 3-methyl-7-phenyl-4(3H)-pteridinone to 3-methyl-7-phenyl-2,4(1H,3H)-pteridinone (3-methyl-7-phenyllumazine [21b]) was observed.
- 23 A. Perez-Rubalcaba and W. Pfleiderer, Ann. Chem., 852 (1983).
- 24 In a few cases precipitation of the substrate occurred on performing the enzymatic oxidation. To avoid this problem stock solutions of the substrates were prepared in 96% of ethanol and diluted with distilled water in such a way that the amount of cosolvents was below 5%.
- 25 Due to the low solubility of 3-alkyl-6-phenyl-4(3H-pteridinone 8-oxides 5, even in a mixture of ethanol and buffer, and the fact that these compounds have their absorption maximum (294–296 nm, log Δϵ = 4.38–4.41) at about the same wavelength where the conversion of 1-meth-ylxanthine to 1-methyluric acid was measured, no accurate data could be obtained.
- 26 I. H. Segel, “ Enzyme Kinetics: Behaviour and Analysis of Rapid Equilibrium Steady-State Enzyme Systems”, Wiley-Interscience, New York, 1975, p 125.
- 27 8-Bromoxanthine is an uncompetitive inhibitor of bovine milk xanthine oxidase with respect to xanthine [28]. Despite the presence of the bulky bromo group this compound interacts with the molybdenum center of xanthine oxidase.
- 28 R. Hille and R. C. Stewart, J. Biol. Chem., 259, 1570 (1984).
