Bosshard, René

Fischer, Berthold

Hesse, Manfred

Schäfer, Andrea

Viscontini, Max

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Fischer eT al.: Metal-tetrahydropterin complexes Pteridines Vol. 4, 1993, pp. 206-209 Short Communication New Results on the Chemistry of Metal-Tetrahydro-Pterin Complexes Berthold Fischer tl § , Andrea Schafer t , Rene Bosshard *, Manfred Hesse t and Max Viscontini t tI Anorganisch-chemisches Institut der Universitat Zurch t Organisch-chemisches lnstitut der Universitat Zurich * Kinderspital, Abteilung Klinische Chemie, der Universitat Zurich Switzerland (Received Janua ry 26, 1993) . Introduction The synthesis of trichloro(6J3-quinonoid-6,7-dihy-dro(8H)-L-biopterin)oxomolybdenum(IV) I, the first molybdenum complex of a quinonoid dihydropterin, has enhanced the interest in metallo-hydrogenated pterin-complexes. These may act as coenzymes of oxi-doreductases in numerous biological reactions (2, 3). ~~ o o a J ".f ~Figure I. Crystal structure of I. It is difficult to obtain product 1 in high yields, because 6J3-5,6,7,8-tetrahydro-L-biopterin (BH4) is ex-pensive; therefore we tried to obtain an analogous product with a pterin, that is easier to synthesize in large quantities. We chose tetrahydropterin as a starting material, which is not chiral and can be obtained very pure. Part 93 (1) § Author to whom correspondence should be addressed. Pteridincs / Vol. 4 / No. 4 Tetrahydropterin 3a reacts with MOVl0 2Ch in the same fashion as BH4 3b to give trichloro(quinonoid-6,7-dihydro(8H)pterin)oxomolybdenum(IV) 2, which we were able to crystallize. The crystal structure of 2 is very similar to that of 1 in respect to bond Figure 2. Crystal structure of 2. length, angles, and confonnation (Figures 1 and 2). The only difference in the crystal structures is the presence of a solvent molecule (methanol) in 1 which is absent in the crystal of 2. Analysis of bond lengths and angles in both crys-tal structures allow us to assume that we obtained quinonoid dihydropterins coordinating a molybde-num(IV) atom with t~e atoms 0(4) and N(5). The quinonoid dihydropterins are monoprotonated at N (2') and possess a N(2')-N(8) mesomeric system (I~ l' and 2~2') (Scheme 1). K. W. Cha et al.: Capillary electrophoretic separation of pteridine compounds 207 2' Scheme 1. In addition one can note that a C(6)-sidechain is not necessary for the formation of a complex. These properties allow one to use tetrahydropterin 3a or some of its derivatives as good model com-pounds for the study of metal-hydropterin coen-zymes of oxidoreductases like phenylalanine hydroxyl-ase. Furthermore one should be able to study the metal-N(S)-methyl-tetrahydropterin coenzymes like homocysteine-methionine methyltransferease. --'(,-------- He Il" ---_. " II II II (';- ('; - CIl,," II (m ell! More than 20 years ago, we were interested in a N(S)-methyl-6,7-diphenyl-tetrahydropterin-iron(II) or-iron(III) complex 5-iron complex). At that time it was easy to obtain 5 and we observed the forma-tion of a coloured compound when mixing together FeCb and 5 (4). o CH5 H N~j(~x~::: 2 H 5 Scheme 2. (4) In the same paper (4) we published a theoretical concept for the formation of a quinonoid-dihydro-pterin-iron complex, in which we summarized the re-sults of our research on the oxidation of tetrahydro-pterins with O 2 (Scheme 2): 1. Necessity of Fe(II) or Fe(III) together with ethyl-enediaminetetraacetic acid (EDTA) as ligand for the activation of O 2 by tetrahydropterins (S), 2. Demonstration that the oxidation of a tetrahy-dropterin 3 to the 7,8-dihydropterin 4 does not occur in one step. Using special conditions we could show. that an intermediate product X is formed. X is only stable if N(2') is disubstituted as it is the case with N(2'),N(2')-dimethyl-tetrahydropterin 3c. In analogy to p-dimethylamino-phenylene-diamine and its p-quinonoid structure, we proposed Xc to be a relative-ly stable quinonoid cation (6). Shortly before, Kaufman showed that during the enzymatic hydroxylation of phenylalanine to tyro-sine BH4 3b, which acts as coenzyme of the hydroxyl-ase, is not directly oxidized to 7,8-dihydro-L-bio-pterin 4b. He proposed the intermediate Y. During the discussion of this paper at the 3rd Symposium on pterin chemistry in Stuttgart, Hemmerich suggest-ed that Y could be a quinonoid-dihydropterin Xb; kaufmann agreed to this suggestion (7). 3. Presentation of a theory implying the formation of radical cations during the oxidation of tetrahy-dropterins (8). 4. We proposed that in the presence of Fe(II) or Fe(III) and EDTA, during the oxidation of 5 to a dihydropterin derivative, an addition of one oxygen atom to the position 4a in 5 takes place (9). S. Finally we obtained experimental proof for the formation of quinonoid trihydropterin radical cat-ions during the oxidation of 5 with HD2 (10). In the same paper we published a possible mechanism of the enzymatic hydroxylation of phenylalanine to Pteridines / Vol. 4 / No.4 208 KW. Cha et uf. : Capillary electrophoretic separation of pteridine compounds Scheme 3. (10) tyrosine in the case of a mixed oxidation (Scheme 3). Two years later at the 4th Symposium of Chemis-try and Biology of Pteridines we extended this me-chanism to the situation of a non-mixed oxidation (11). In all experiments using 5 we observed a loss of the N(5)-methyl group during the oxidation. Only 6,7-diphenyl-pterin 6 was isolated as the final pro-duct (12). °2 Fe(lII) 5 6 Since it is reasonable to replace BH4 by tetrahy-dropterin in the formation of metal complexes with molybdenum, we started to repeat the experiments mentioned above with N(5)-methyl-tetrahdropterin 7 and a Fe(III) complex of the composition Fe(acac)3 8 (acac=acetylacetonate). Without H 20 2 as an oxi-dant, we hoped to find an experimental confirma-tion for the existence of the radical cations, which we proposed 25 years ago. N(5)-methyl-tetrahydropterin 7 can be obtained as a pure and very stable dihydrochloride in a simple fashion by a small modification of Matsuura's me-thod (13). The important step was to find a way to detect the complex formed between 7 and 8. An electrospray-ionisation-mass spectrum (ESI-MS) in the positive ion mode was run of compound 7 ·2 Hel in a 10- 3 M solution at pH 2-3 in methan-ol or a mixture of acetonitrile and water. Both show the [M + GJ + signal at m/z 182 of the proto-nated starting material 7 as well as other protonated molecule clusters of 7. The formation of clusters con-Pteridines / VoL 4 / No. 4 tammg up to seven molecules of 7 are most likely to be due to the high concentration of the solution. This is in accordance with analogous experiments with arginine (14). The ESI-MS of a 1:1 molar solution of 7 and 8 show protonated clusters of 7 and 8 and a new signal at m/z 435, which corresponds 'most likely to complex 9. Arguing from analogy with complexes 1 and l' one could propose complex 9 to be a radi-cal cation. Figure 3. Electrospray-ionisation-mass spectrum of 7 and 8, in a 1:1 molar ratio in acetonitrile/water, pH 2-3. The signal at m/z 435 corresponds to the proposed radical cation com-plex 9. So far the best conditions for the formation of the metal complex 9 with a molecular weight of 435 are strict exclusion of oxygen and a 1:1 molar ratio of 7 and 8 in acetonitrile with the smallest amount of water necessary to keep 7 in solution (Figure 3). Figure 4. ESR spectrum 1:I molar solution of 7 and 8 after 24 hours under argon, acetonitrile/water, pH 2-3.  K. W. Cha et al.: Capillary electrophoretic separation of pteridine compounds 209 Cat.ioni c t.rihydropt.erin radi cal 10 In the absence of oxygen compound 9 is stable for more than 24 hours. Even after this time the solution shows the ESR signal of a stable radical. The spectrum corresponds to known ESR signal of a cationic trihydropterin radical 10 formed by H 20 2 oxidation of tetrahydropterin (G value = 2.003, split-ting ca. 10 G) (10, 15) (Figure 4). A full paper will be published in Helvetica Chimica Acta. Acknowledgement We thank Dr. H. Paul and Prof. Dr. H. Fischer of the Physikalisch-chemisches Institut of the Uni-versity of Zurich for the measurement f the ESR spectrum. References 1. Part 92: Adler C, Curtius H.-Ch, Wetzel E, Viscontini M. Giudici TA, Blaskovics M, Rolland M, Guibaud P, Helv. Chim. Acta 1992; 75: 1237. 2. Fischer B, Strahle J, Viscontini M, Helv. Chim. Acta 1991; 74: 1544. 3. Fischer B, Strahle J, Viscontini M, Pteridines, 1992; 3: 91. 4. Viscontini M , Okada T, He1v. Chim. Acta 1%7; 50: 18 45. 5. Bobst A Viscontini M, Helv. Chim. Acta 1966; 49: 884. 6. Viscontini M, Bobst A He1v. Chim. Acta 1966; 49: 18 15. 7. Kaufman S. in Pteridine Chemistry (Pfleiderer W, and Taylor EC eds) pp. 307-326, Pergamon Press, Oxofrd, Lo-ndon 1966. . 8. Viscontini M, Leidner HA Mattern G, Okada T, Helv. Chim. Acta 1966; 49: 1911. 9. Viscontini M, Okada T, Helv. Chim. Acta 1967; 50: 1492. 10. Ehrenberg A, Hemmerich P , Muller F, Okada T , Viscon-tini M, Helv. Chim. Acta 1967; 50: 411. 11. Viscontini M, in Chemistry and Biology of Pteridines (lwai K, et al. eds) pp. 217-224, Int. Acad. Print. Co., Tokyo, Japan 1970. 12. Viscontini M, Okada T He1v. Chim. Acta 1969; 52: 306. l3. matsuura S, in Chemistry and Biology ofPteridines (Iwai K et al. eds) pp. 35-42, Int. Acad. Print. Co., Tokyo, Japan 1970. 14. Meng CK, Fenn JB, Org. Mass. Spectr 1991; 26: 542. 15. Bobst A Helv. Chim. Acta 1968; 51: 607. Pteridines / Vol. 4 / No.4 

New Results on the Chemistry of Metal-Tetrahydro-Pterin Complexes

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