Novel and Artificial Enediyne DNA Cleaving Molecules: Molecular Design, Chemical Synthesis, and Evaluation

Kazunobu Toshima, Masaya Nakata, Shiuchi Matsumura

Research output: Contribution to journalArticle

Abstract

The molecular design and chemical synthesis of novel and artificial enediyne classes of DNA cleaving molecules 1∼4, and their chemical and DNA cleaving profiles are described. The enediyne sulfides 1a∼1 were synthesized via the coupling of the vinyl iodide 8 and the protected propargyl alcohol 9, and the intramolecular cyclization of the dibromide 17. 1b was found to cycloaromatize by 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) in 1,4-cyclohexadiene through radical pathways and by a hydroxy anion in dimethyl sulfoxide-Tris-HCl, pH 8.5 buffer through a polar pathway, 1a∼1 cleaved DNA under weakly alkaline conditions, and 1e, 1k and 1l, all of which have a DNA intercalatable moiety, exhibited strong DNA cleaving activities with the identical high purine base (G>A) selectivity. The enediyne triols 2a∼c were prepared from xylitol (19) via the conversion of the keto-aldehyde 24 into the keto-enediyne 25 by an intramolecular aldol reaction. 2a was also cycloaromatized in a manner similar to that for the enediyne sulfide, and 2a∼c showed guanine-specific DNA cleavages under weakly alkaline conditions. The enynallene sulfones 3a∼f were obtained by m-CPBA oxidation of the corresponding enediyne sulfides. 3c was cycloaromatized by DBU through both radical and polar pathways. 3a∼f cleaved DNA at any DNA-base site under weakly alkaline conditions, and 3d∼f possessing a hydrophilic moiety exhibited stronger DNA cleavages. The dienediynes 4a∼c were synthesized from 25. 4c possessing acetoxy groups at the propargylic positions was cycloaromatized by methyl thioglycolate through radical pathways, and cleaved DNA at any pH with guanine-base selectivity. Furthermore, the DNA cleaving activity of 4c significantly increased in the presence of methyl thioglycolate.

Original languageEnglish
Pages (from-to)51-61
Number of pages11
JournalYuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry
Volume54
Issue number6
Publication statusPublished - 1996

Fingerprint

Enediynes
Molecules
DNA
Sulfides
Guanine
Xylitol
Sulfones
Cyclization
Dimethyl Sulfoxide
Aldehydes
Anions

Keywords

  • Artificial restriction enzyme
  • Chemical synthesis
  • Cycloaromatization
  • Diradical
  • DNA cleavage, Alkylation of dNA
  • Enediyne antibiotics
  • Molecular design
  • Neocarzinostatin chromophore
  • Sanger protocol

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Novel and Artificial Enediyne DNA Cleaving Molecules : Molecular Design, Chemical Synthesis, and Evaluation. / Toshima, Kazunobu; Nakata, Masaya; Matsumura, Shiuchi.

In: Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry, Vol. 54, No. 6, 1996, p. 51-61.

Research output: Contribution to journalArticle

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N2 - The molecular design and chemical synthesis of novel and artificial enediyne classes of DNA cleaving molecules 1∼4, and their chemical and DNA cleaving profiles are described. The enediyne sulfides 1a∼1 were synthesized via the coupling of the vinyl iodide 8 and the protected propargyl alcohol 9, and the intramolecular cyclization of the dibromide 17. 1b was found to cycloaromatize by 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) in 1,4-cyclohexadiene through radical pathways and by a hydroxy anion in dimethyl sulfoxide-Tris-HCl, pH 8.5 buffer through a polar pathway, 1a∼1 cleaved DNA under weakly alkaline conditions, and 1e, 1k and 1l, all of which have a DNA intercalatable moiety, exhibited strong DNA cleaving activities with the identical high purine base (G>A) selectivity. The enediyne triols 2a∼c were prepared from xylitol (19) via the conversion of the keto-aldehyde 24 into the keto-enediyne 25 by an intramolecular aldol reaction. 2a was also cycloaromatized in a manner similar to that for the enediyne sulfide, and 2a∼c showed guanine-specific DNA cleavages under weakly alkaline conditions. The enynallene sulfones 3a∼f were obtained by m-CPBA oxidation of the corresponding enediyne sulfides. 3c was cycloaromatized by DBU through both radical and polar pathways. 3a∼f cleaved DNA at any DNA-base site under weakly alkaline conditions, and 3d∼f possessing a hydrophilic moiety exhibited stronger DNA cleavages. The dienediynes 4a∼c were synthesized from 25. 4c possessing acetoxy groups at the propargylic positions was cycloaromatized by methyl thioglycolate through radical pathways, and cleaved DNA at any pH with guanine-base selectivity. Furthermore, the DNA cleaving activity of 4c significantly increased in the presence of methyl thioglycolate.

AB - The molecular design and chemical synthesis of novel and artificial enediyne classes of DNA cleaving molecules 1∼4, and their chemical and DNA cleaving profiles are described. The enediyne sulfides 1a∼1 were synthesized via the coupling of the vinyl iodide 8 and the protected propargyl alcohol 9, and the intramolecular cyclization of the dibromide 17. 1b was found to cycloaromatize by 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) in 1,4-cyclohexadiene through radical pathways and by a hydroxy anion in dimethyl sulfoxide-Tris-HCl, pH 8.5 buffer through a polar pathway, 1a∼1 cleaved DNA under weakly alkaline conditions, and 1e, 1k and 1l, all of which have a DNA intercalatable moiety, exhibited strong DNA cleaving activities with the identical high purine base (G>A) selectivity. The enediyne triols 2a∼c were prepared from xylitol (19) via the conversion of the keto-aldehyde 24 into the keto-enediyne 25 by an intramolecular aldol reaction. 2a was also cycloaromatized in a manner similar to that for the enediyne sulfide, and 2a∼c showed guanine-specific DNA cleavages under weakly alkaline conditions. The enynallene sulfones 3a∼f were obtained by m-CPBA oxidation of the corresponding enediyne sulfides. 3c was cycloaromatized by DBU through both radical and polar pathways. 3a∼f cleaved DNA at any DNA-base site under weakly alkaline conditions, and 3d∼f possessing a hydrophilic moiety exhibited stronger DNA cleavages. The dienediynes 4a∼c were synthesized from 25. 4c possessing acetoxy groups at the propargylic positions was cycloaromatized by methyl thioglycolate through radical pathways, and cleaved DNA at any pH with guanine-base selectivity. Furthermore, the DNA cleaving activity of 4c significantly increased in the presence of methyl thioglycolate.

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KW - Enediyne antibiotics

KW - Molecular design

KW - Neocarzinostatin chromophore

KW - Sanger protocol

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