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Titel:Synthesis of cysteine sulfoxides and related compounds occurring in wild onions
Autor:Feizabad, Mohammad Sadegh
Weitere Beteiligte: Keusgen, Michael (Prof. Dr.)
Erscheinungsjahr:2019
URI:http://archiv.ub.uni-marburg.de/diss/z2019/0492
DOI: https://doi.org/10.17192/z2019.0492
URN: urn:nbn:de:hebis:04-z2019-04921
DDC:615 Pharmacology & therapeutics, prescription drugs
Titel(trans.):Synthese von Cysteinsulfoxiden und verwandten Verbindungen in Wildzwiebeln

Dokument

Schlagwörter:
Cysteinsulfoxide, heteroaromatic cysteine sulfoxides, Pyrrolcysteinsulfoxide, Cysteine sulfoxides, thiophene cysteine sulfoxides, Heteroaromatische Cysteinsulfoxide, pyrrole cysteine sulfoxides, Thiophencysteinsulfoxide, S-(N-benzylpyrrol-2-yl)cysteine ,S-(2-pyrrolyl)cysteine,S-(N-methylpyrrol-2-yl)cysteine, S-(2-thienyl)cysteine-S-oxide,

Summary:
Cysteine sulfoxides are important secondary compounds in Allium sativum and A. cepa, and have been known as substrates specific for enzyme alliinase. Different types of cysteine sulfoxides have been identified in many of Allium species, of which methiin, alliin, propiin, butiin and marasmin are some of the best-known and best-studied ones. S-(2-pyrrolyl)cysteine-S-oxide is one of heteroaromatic cysteine sulfoxides containing a pyrrole ring. It has been largely reported in A. rosenorum, A. macleanii, A. giganteum, and A. carolanianum of subgen. Melanochrommyum. S-(2-pyrrolyl)cysteine-S-oxide is converted to the red pigment or 2,2′-epidithio-3,3′-dipyrrole under alliinase reaction. To understand the molecular structure, pharmacology, and medicinal usage of this interesting pigment, the synthesis of this type of cysteine sulfoxides and their homologues with enough similar characteristics is necessitated. In this work, six compounds were synthesized either as a sulfoxide or sulfide that contained: S-(N-benzylpyrrol-2-yl)cysteine (47% yield); S-(N-methylpyrrol-2-yl)cysteine (23% yield); S-(2-pyrrolyl)cysteine (35% yield); S-(2-thienyl)cysteine (93% yield); S-(N-benzylpyrrol-2-yl)cysteine-S-oxide (30% yield) and; S-(2-thienyl)cysteine-S-oxide (48% yield). The first four compounds were synthesized as sulfides and two latter as cysteine sulfoxides. The first three abovementioned products were synthesized using heteroaromatic N-benzyl pyrrole, N-methyl pyrrole, and pyrrole in combination with thiourea and KI/I2, which was followed by alkalization of the reaction mixture. 3-Chloro-L-alanine, as the key primary compound, was added to the mixture and heated up to 100˚C for 2 h under argon protection. Final products, if stable, could be purified using preparative-HPLC or re-precipitated using diethylether dissolved in low amounts of methanol. A different method was conducted to synthesize S-(2-thienyl)cysteine, as compared to method used to synthesize the first three products. A nucleophilic substitution reaction was carried out between sulfur compounds (as nucleophile) and 3-chloro-L-alanine. The next step in obtaining cysteine sulfoxides was to oxidize the synthesized products. Out of six products, S-(2-thienyl)cysteine and S-(N-benzylpyrrol-2-yl)cysteine were successfully oxidized using H2O2 in water or acetic acid, resulting in S-(2-thienyl)cysteine-S-oxide and S-(N-benzylpyrrol-2-yl)cysteine-S-oxide. If they were stable, the purification of these products was performed using preparative HPLC. The oxidation of the remaining products (S-(N-benzylpyrrol-2-yl)cysteine, S-(2-thienyl)cysteine, S-(N-methylpyrrol-2-yl)cysteine and S-(2-pyrrolyl)cysteine), was not possible because of their high instability and polymerization against light, oxygen, and temperature. Additionally, weak oxidants, such as MMPP, were unable to oxidize these compounds. Lastly, an enzymatic test was conducted to estimate the reactivity of all the synthesized products to alliinase. To adjust the optimum pH for the enzyme alliinase, alliinase buffer was added to the products, which were dissolved in water. The reaction was followed by adding cyclohexane (organic phase) to the reaction mixture and incubating the mixture for 2 h: in the end, the organic phase was separated, dried with MgSO4, and evaporated. Alliin was used as positive control. S-(2-thienyl)thiophene-2-sulfinothioate was successfully separated and identified using HPLC-MS.

Zusammenfassung:
Cysteine sulfoxides are important secondary compounds in Allium sativum and A. cepa, and have been known as substrates specific for enzyme alliinase. Different types of cysteine sulfoxides have been identified in many of Allium species, of which methiin, alliin, propiin, butiin and marasmin are some of the best-known and best-studied ones. S-(2-pyrrolyl)cysteine-S-oxide is one of heteroaromatic cysteine sulfoxides containing a pyrrole ring. It has been largely reported in A. rosenorum, A. macleanii, A. giganteum, and A. carolanianum of subgen. Melanochrommyum. S-(2-pyrrolyl)cysteine-S-oxide is converted to the red pigment or 2,2′-epidithio-3,3′-dipyrrole under alliinase reaction. To understand the molecular structure, pharmacology, and medicinal usage of this interesting pigment, the synthesis of this type of cysteine sulfoxides and their homologues with enough similar characteristics is necessitated. In this work, six compounds were synthesized either as a sulfoxide or sulfide that contained: S-(N-benzylpyrrol-2-yl)cysteine (47% yield); S-(N-methylpyrrol-2-yl)cysteine (23% yield); S-(2-pyrrolyl)cysteine (35% yield); S-(2-thienyl)cysteine (93% yield); S-(N-benzylpyrrol-2-yl)cysteine-S-oxide (30% yield) and; S-(2-thienyl)cysteine-S-oxide (48% yield). The first four compounds were synthesized as sulfides and two latter as cysteine sulfoxides. The first three abovementioned products were synthesized using heteroaromatic N-benzyl pyrrole, N-methyl pyrrole, and pyrrole in combination with thiourea and KI/I2, which was followed by alkalization of the reaction mixture. 3-Chloro-L-alanine, as the key primary compound, was added to the mixture and heated up to 100˚C for 2 h under argon protection. Final products, if stable, could be purified using preparative-HPLC or re-precipitated using diethylether dissolved in low amounts of methanol. A different method was conducted to synthesize S-(2-thienyl)cysteine, as compared to method used to synthesize the first three products. A nucleophilic substitution reaction was carried out between sulfur compounds (as nucleophile) and 3-chloro-L-alanine. The next step in obtaining cysteine sulfoxides was to oxidize the synthesized products. Out of six products, S-(2-thienyl)cysteine and S-(N-benzylpyrrol-2-yl)cysteine were successfully oxidized using H2O2 in water or acetic acid, resulting in S-(2-thienyl)cysteine-S-oxide and S-(N-benzylpyrrol-2-yl)cysteine-S-oxide. If they were stable, the purification of these products was performed using preparative HPLC. The oxidation of the remaining products (S-(N-benzylpyrrol-2-yl)cysteine, S-(2-thienyl)cysteine, S-(N-methylpyrrol-2-yl)cysteine and S-(2-pyrrolyl)cysteine), was not possible because of their high instability and polymerization against light, oxygen, and temperature. Additionally, weak oxidants, such as MMPP, were unable to oxidize these compounds. Lastly, an enzymatic test was conducted to estimate the reactivity of all the synthesized products to alliinase. To adjust the optimum pH for the enzyme alliinase, alliinase buffer was added to the products, which were dissolved in water. The reaction was followed by adding cyclohexane (organic phase) to the reaction mixture and incubating the mixture for 2 h: in the end, the organic phase was separated, dried with MgSO4, and evaporated. Alliin was used as positive control. S-(2-thienyl)thiophene-2-sulfinothioate was successfully separated and identified using HPLC-MS.


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