Latent Enamine Functionality of 5-Methyl-2,3-dihydropyrazines

Abstract

Dihydropyrazine derivatives (DHPs) derived from dimerization of amino sugars, such as glucosamine and mannosamine, spontaneously generate carbon-centered radicals and exhibit DNA strand-breaking activity, which may be related to the apoptotic activity of amino sugars.1,2) The DHP derivative 3,6-dihydropyrazine-2,5-dipropionic acid is formed by dimerization of 5-aminolevulic acid, which is accumulated in congenital and acquired hepatic porphyrias, such as acute intermittent porphyria, and might induce hepatocellular carcinoma.3) The dimerization of these aaminocarbonyl compounds proceeds via a non-enzymatic process under physiological conditions to afford 2,5-DHPs initially, and these might be isomerized to other types of DHPs as a consequence of resonance stabilization, and/or oxidized to pyrazines. However, the thermal and chemical instability of DHPs has made it difficult to investigate their chemical properties and biological functions in detail.Previously we reported the preparation of simple DHP derivatives such as 5,6-dimethyl-2,3-DHP (1) and 2,2,5,6-tetramethyl-2,3-DHP (2) by the reaction of diacetyl and ethylenediamines in diethyl ether according to Ishiguro's procedure (Chart 1).4) These methyl-substituted DHPs showed DNA strand-breaking activity with potency comparable to that of DHP formed from D-glucosamine.5) During mechanistic investigations, we found that compound 2 dimerized at room temperature without any catalyst.6,7) Semi-empirical PM3 molecular orbital (MO) calculation suggested the feasibility of tautomerization from 2 (diimine form) to 2exo (enamine form) during the dimerization reaction. Further, from a biological viewpoint, the reduction of Koopman's ionization potential value (IPϭϪE HOMO ) resulting from tautomerization of DHPs to the enamine form should be closely related to the DNA-damaging ability. 8) However, there is no evidence for the formation of an enamine moiety, such as 1exo and 2exo. In this study, we explored the possible formation of enamine tautomers of DHPs by means of theoretical and empirical methods. ExperimentalComputation The Spartan '06 and '08 for Windows software 9) with the density functional theory (DFT) B3LYP 10 /6-311ϩG** basis set was employed to estimate the global minimum energy of the optimized structures of compounds and transition states (TS). Zero point energy was not corrected. The obtained TS geometry was evaluated by means of vibrational frequency analysis and intrinsic reaction coordinate (IRC) calculation. The solvation effect of water was approximated by way of the SM8 model 11 at the DFT B3LYP/6-31G* basis set level, because the SM8 model did not cover 6-311ϩG** basis set.Experimental All chemicals were available in commercial. Phenyl propane-1,2-dione, N-methyl ethylenediamine and phenyl isocyanate were purchased from Tokyo Chemical Industry Co., Ltd., ethylenediamine and acetonitrile were from Kanto Chemical Co., Inc. Deuterium oxide and pyridine-d 5 were also purchased from CEA, and DMSO-d 6 was from Isotec Inc. Melting points were measured wi...

Identification of dihydropyrazine-glutathione adducts

“…1). The highly reactive nature of the exo-methylene group of DHP has been attributed to its latent enamine functionality, and this result has been confirmed both experimentally and theoretically (Ito et al, 2010). The low energy distribution of the highest occupied molecular orbital (HOMO) on the exo-methylene group of the DHP moiety would allow it undergo nucleophilic addition reactions with various biological thiols, including cysteine and GSH.…”

Chemoenzymatic synthesis of 3-ethyl-2,5-dimethylpyrazine by L-threonine 3-dehydrogenase and 2-amino-3-ketobutyrate CoA ligase/L-threonine aldolase

“…Finally, DHP tautomerizes and undergoes nucleophilic addition to acetaldehyde to synthesize EDMP. Other research groups reported that the DHP is easily oxidized under mild condition to form 2,5-dimethylpyrazine (DMP) 33 , 34 , suggesting that immediate reaction of DHP with acetaldehyde increases the production of EDMP. To confirm this point, we compared production rates of EDMP and DMP by changing the timing of acetaldehyde addition (Supplementary Table 6 ).…”

Conformationally Driven Ru(II)-Catalyzed Multiple ortho-C–H Bond Activation in Diphenylpyrazine Derivatives in Water: Where Is the Limit?

“…The pyrazine scaffold is one of the privileged azaheterocyclic structural motifs in many natural products [44] and synthetic compounds [45] with biological activities, as well as in functional materials [46]. 2,3-Dihydropyrazines, which are direct precursors of pyrazines, are known to have an important role as flavorants [47] and are assumed to actively participate in DNA strand cleavage [48][49][50] and cyclooxygenase inhibition [51]. In addition, the pyrazine derivatives can efficiently act as ligands in the construction of metallosupramolecular architectures because of their two N-coordinating sites [52][53][54][55][56][57], as well as building blocks in the design of photoluminescence devices [46].…”