Synthesis and DNA Strand Breakage Activity of Some 1,4-Diazepines.

Mibu, Nobuko; Yukawa, Miho; Kashige, Nobuhiro; Iwase, Yukiko; Goto, Yoshinobu; Miake, Fumio; Yamaguchi, Tadatoshi; Ito, Shigeru; Sumoto, Kunihiro

doi:10.1248/cpb.51.27

Cited by 14 publications

(7 citation statements)

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“…TLC was used to monitor the completion of the reaction; the structures of products were assessed by interpretation of IR and NMR spectra obtained. The spectroscopic data of IR and 1 H-NMR are in agreement with the structure of fused 1, 4-diazepine derivatives 3,4,6,7,8,9,10 .…”

Section: Resultssupporting

confidence: 76%

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2011

IJPSR

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Section: Resultssupporting

confidence: 76%

Untitled

2011

IJPSR

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“…[5][6][7] The preferential reactivity of DHPs may be enhanced by the formation of an enamine moiety and the breakage activity also might require this isomerization. To test this hypothesis we attempted to synthesize a hexahydroquinoxaline compound, where the exo-type isomer predominates 14) due to steric factors in the fused ring (Chart 3).…”

Section: Resultsmentioning

confidence: 99%

The Relationship between the Chemical Structures of Dihydropyrazine Derivatives and DNA Strand-Breakage Activity

et al. 2007

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We have previously described the DNA strand-breaking activity 1,2) and other characteristics (e.g., generation of radical species 3,4) and high chemical reactivity 5-7) ) of dihydropyrazines (DHPs) in vitro. More recently, we have examined the biological effects of DHPs, such as induction of apoptosis 8) and mutagenesis, 9) in vivo. The various phenomena caused by DHPs cannot be explained on the basis of one particular reaction mechanism. In this paper, we attempt to illustrate the relationship of the chemical structure of DHPs on DNA strand scission. ExperimentalSynthesis of Dihydropyrazine Derivatives The dihydropyrazine derivatives ( Fig. 1) employed were synthesized by the condensation of diketones and diamines. 2,3-Dihydro-5,6-dimethylpyrazine (1), 2,3-dihydro-2,5,6-trimethylpyrazine (2), 2,3-dihydro-2,2,5,6-tetramethylpyrazine (3), cis-2, 3-dimethyl-5,6,7,8,9,10-hexahydroquinoxaline (4-cis) and trans-2,3-dimethyl-5,6,7,8,9,10-hexahydroquinoxaline (4-trans) were synthesized by the method of Yamaguchi et al.1) Their derivatives (3a, 7) 2a, 7) 1c, 7) 1b 5) ) and dihydrofructosazine 10) were synthesized according to literature procedures, and 1a was synthesized from aminoacetone hydrochloride 11) by dehydrochlorination.10) Similar methods were also used to replace the methyl group of 1 and 4-trans by a phenyl group to generate 2,3-dihydro-5-methyl-6-phenylpyrazine (5) 12) and trans- 2-methyl-3-phenyl-5,6,7,8,9,10-hexahydroquinoxaline (6), 12) respectively (Table 1), and the mixture (7) 13) of 2, 3,5,6,7,2,3,5,6,.Assay of DNA Strand-Breaking Activity The method to assess the DNA strand-breakage activity of DHPs, using a covalently closed circular duplex DNA (ccc-DNA) of plasmid pBR322 was described previously. Dihydropyrazine, a compound derived from sugars, possesses DNA strand-breakage activity. The relationship between the activity as assayed using pBR 322 ccc-DNA and the chemical structures of derivatives of dihydropyrazine (DHPs) has been investigated. The addition of Cu 2؉ enhanced the activity remarkably. The introduction of a methyl or phenyl group onto the DHP ring or a cyclohexyl group fused onto the DHP ring also increased the activity. These properties indicated that the activity was due to the facility of electron release from the DHP ring, followed by radical generation. The determination of ionization potential and electrostatic potential values, and bond dissociation energy via semi-empirical MO calculations suggested strongly that the activity is induced by a DHP ring structure that contains a configuration suitable for hyperconjugation. 1) Semi-empirical MO Calculations

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“…The IR spectrum of the uncyclized product obtained shows an intense peak at 1670 cm -1 , which may be due to multiple condensation of ethanedione with 1,3-propanediamine even when equimolar quantities of ethanedione and 1,3-propanediamine are reacted [12].…”

Section: II Iiimentioning

confidence: 96%