Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization

Anna G. Lyapunova, Natalia A. Danilkina, Andrey M. Rumyantsev, A. F. Khlebnikov, Mikhail V. Chislov, Galina L. Starova, Elena V. Sambuk, Anastasia I. Govdi, Stefan Brase, Irina A. Balova

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothio-phene, benzene, and cinnoline annulated 9- and 10-membered enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholas type macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropyl-substituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin.

Original languageEnglish
Pages (from-to)2788-2801
Number of pages14
JournalJournal of Organic Chemistry
Volume83
Issue number5
DOIs
StatePublished - 2 Mar 2018

Keywords

  • TRANSITION-STATE STABILIZATION
  • NICHOLAS REACTION
  • ELECTROPHILIC CYCLIZATION
  • ANTICANCER ANTIBIOTICS
  • CLICK CHEMISTRY
  • ENYNE-ALLENES
  • COMPLEXES
  • RING
  • CONSTRUCTION
  • CYCLOAROMATIZATION

Cite this

Lyapunova, Anna G. ; Danilkina, Natalia A. ; Rumyantsev, Andrey M. ; Khlebnikov, A. F. ; Chislov, Mikhail V. ; Starova, Galina L. ; Sambuk, Elena V. ; Govdi, Anastasia I. ; Brase, Stefan ; Balova, Irina A. / Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization. In: Journal of Organic Chemistry. 2018 ; Vol. 83, No. 5. pp. 2788-2801.
@article{4ec3acd2e00b4c1d8883ccc4f804d106,
title = "Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization",
abstract = "To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothio-phene, benzene, and cinnoline annulated 9- and 10-membered enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholas type macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropyl-substituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin.",
keywords = "TRANSITION-STATE STABILIZATION, NICHOLAS REACTION, ELECTROPHILIC CYCLIZATION, ANTICANCER ANTIBIOTICS, CLICK CHEMISTRY, ENYNE-ALLENES, COMPLEXES, RING, CONSTRUCTION, CYCLOAROMATIZATION",
author = "Lyapunova, {Anna G.} and Danilkina, {Natalia A.} and Rumyantsev, {Andrey M.} and Khlebnikov, {A. F.} and Chislov, {Mikhail V.} and Starova, {Galina L.} and Sambuk, {Elena V.} and Govdi, {Anastasia I.} and Stefan Brase and Balova, {Irina A.}",
year = "2018",
month = "3",
day = "2",
doi = "10.1021/acs.joc.7b03258",
language = "Английский",
volume = "83",
pages = "2788--2801",
journal = "Journal of Organic Chemistry",
issn = "0022-3263",
publisher = "American Chemical Society",
number = "5",

}

Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization. / Lyapunova, Anna G.; Danilkina, Natalia A.; Rumyantsev, Andrey M.; Khlebnikov, A. F.; Chislov, Mikhail V.; Starova, Galina L.; Sambuk, Elena V.; Govdi, Anastasia I.; Brase, Stefan; Balova, Irina A.

In: Journal of Organic Chemistry, Vol. 83, No. 5, 02.03.2018, p. 2788-2801.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Relative Reactivity of Benzothiophene-Fused Enediynes in the Bergman Cyclization

AU - Lyapunova, Anna G.

AU - Danilkina, Natalia A.

AU - Rumyantsev, Andrey M.

AU - Khlebnikov, A. F.

AU - Chislov, Mikhail V.

AU - Starova, Galina L.

AU - Sambuk, Elena V.

AU - Govdi, Anastasia I.

AU - Brase, Stefan

AU - Balova, Irina A.

PY - 2018/3/2

Y1 - 2018/3/2

N2 - To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothio-phene, benzene, and cinnoline annulated 9- and 10-membered enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholas type macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropyl-substituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin.

AB - To find promising analogues of naturally occurring enediyne antibiotics with a sufficient reactivity in the Bergman cyclization and moderately stable under isolation and storage, a scale of relative enediynes reactivity was created on the basis of calculated free activation energies for the Bergman cyclization within 12 known and new benozothio-phene, benzene, and cinnoline annulated 9- and 10-membered enediynes. To verify the predicted reactivity/stability balance, three new carbocyclic enediynes fused to a benzothiophene core bearing 3,4,5-trimethoxybenzene, fluoroisopropyl, and isopropenyl substituents were synthesized using the Nicholas type macrocyclization. It was confirmed that annulation of a 3,4,5-trimethoxybenzene moiety to a 10-membered enediyne macrocycle imparts high reactivity to an enediyne while also conferring instability under ambient temperature. Fluoroisopropyl-substituted 10-membered enediyne from the opposite end of the scale was found to be stable while moderately reactive in the Bergman cyclization. Along with the experimentally confirmed moderate reactivity (DSC kinetic studies), (fluoroisopropyl)enediyne showed a significant DNA damaging activity in plasmid cleavage assays comparable with the known anticancer drug Zeocin.

KW - TRANSITION-STATE STABILIZATION

KW - NICHOLAS REACTION

KW - ELECTROPHILIC CYCLIZATION

KW - ANTICANCER ANTIBIOTICS

KW - CLICK CHEMISTRY

KW - ENYNE-ALLENES

KW - COMPLEXES

KW - RING

KW - CONSTRUCTION

KW - CYCLOAROMATIZATION

U2 - 10.1021/acs.joc.7b03258

DO - 10.1021/acs.joc.7b03258

M3 - статья

VL - 83

SP - 2788

EP - 2801

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

SN - 0022-3263

IS - 5

ER -