A strategy for identifying novel, mechanistically unique inhibitors of topoisomerase I

Sidney Hecht, David E. Berry, Laurie J. MacKenzie, Robert W. Busby, Christopher A. Nasuti

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

While the design of molecules that inhibit or antagonize the functions of specific macromolecules is now well precedented, in many cases the structural information requisite to the design process is lacking. The tools of molecular biology can now furnish the target macromolecules for use in mechanism-based exploration; highly defined assays can be devised based upon the known biochemistry of these macromolecules to permit the discovery of novel inhibitors or antagonists present in chemical collections. Presently, we describe a set of assays directed toward the discovery of novel inhibitors of eukaryotic topoisomerase I, an enzyme critical to maintenance of chromosomal DNA topology and therefore essential for normal replication and transcription. The identification of chebulagic acid as an extraordinarily potent and mechanistically novel inhibitor of topoisomerase I illustrates the potential of this approach.

Original languageEnglish (US)
Pages (from-to)401-413
Number of pages13
JournalJournal of Natural Products
Volume55
Issue number4
StatePublished - 1992
Externally publishedYes

Fingerprint

Topoisomerase I Inhibitors
DNA topoisomerase
Macromolecules
Assays
assays
Biochemistry
biochemistry
topology
molecular biology
Molecular Biology
antagonists
Type I DNA Topoisomerase
Molecular biology
transcription (genetics)
Maintenance
Transcription
acids
DNA
Enzymes
enzymes

ASJC Scopus subject areas

  • Plant Science
  • Chemistry (miscellaneous)
  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Hecht, S., Berry, D. E., MacKenzie, L. J., Busby, R. W., & Nasuti, C. A. (1992). A strategy for identifying novel, mechanistically unique inhibitors of topoisomerase I. Journal of Natural Products, 55(4), 401-413.

A strategy for identifying novel, mechanistically unique inhibitors of topoisomerase I. / Hecht, Sidney; Berry, David E.; MacKenzie, Laurie J.; Busby, Robert W.; Nasuti, Christopher A.

In: Journal of Natural Products, Vol. 55, No. 4, 1992, p. 401-413.

Research output: Contribution to journalArticle

Hecht, S, Berry, DE, MacKenzie, LJ, Busby, RW & Nasuti, CA 1992, 'A strategy for identifying novel, mechanistically unique inhibitors of topoisomerase I', Journal of Natural Products, vol. 55, no. 4, pp. 401-413.
Hecht, Sidney ; Berry, David E. ; MacKenzie, Laurie J. ; Busby, Robert W. ; Nasuti, Christopher A. / A strategy for identifying novel, mechanistically unique inhibitors of topoisomerase I. In: Journal of Natural Products. 1992 ; Vol. 55, No. 4. pp. 401-413.
@article{f935dee24b634d46acdb55eb97762709,
title = "A strategy for identifying novel, mechanistically unique inhibitors of topoisomerase I",
abstract = "While the design of molecules that inhibit or antagonize the functions of specific macromolecules is now well precedented, in many cases the structural information requisite to the design process is lacking. The tools of molecular biology can now furnish the target macromolecules for use in mechanism-based exploration; highly defined assays can be devised based upon the known biochemistry of these macromolecules to permit the discovery of novel inhibitors or antagonists present in chemical collections. Presently, we describe a set of assays directed toward the discovery of novel inhibitors of eukaryotic topoisomerase I, an enzyme critical to maintenance of chromosomal DNA topology and therefore essential for normal replication and transcription. The identification of chebulagic acid as an extraordinarily potent and mechanistically novel inhibitor of topoisomerase I illustrates the potential of this approach.",
author = "Sidney Hecht and Berry, {David E.} and MacKenzie, {Laurie J.} and Busby, {Robert W.} and Nasuti, {Christopher A.}",
year = "1992",
language = "English (US)",
volume = "55",
pages = "401--413",
journal = "Journal of Natural Products",
issn = "0163-3864",
publisher = "American Chemical Society",
number = "4",

}

TY - JOUR

T1 - A strategy for identifying novel, mechanistically unique inhibitors of topoisomerase I

AU - Hecht, Sidney

AU - Berry, David E.

AU - MacKenzie, Laurie J.

AU - Busby, Robert W.

AU - Nasuti, Christopher A.

PY - 1992

Y1 - 1992

N2 - While the design of molecules that inhibit or antagonize the functions of specific macromolecules is now well precedented, in many cases the structural information requisite to the design process is lacking. The tools of molecular biology can now furnish the target macromolecules for use in mechanism-based exploration; highly defined assays can be devised based upon the known biochemistry of these macromolecules to permit the discovery of novel inhibitors or antagonists present in chemical collections. Presently, we describe a set of assays directed toward the discovery of novel inhibitors of eukaryotic topoisomerase I, an enzyme critical to maintenance of chromosomal DNA topology and therefore essential for normal replication and transcription. The identification of chebulagic acid as an extraordinarily potent and mechanistically novel inhibitor of topoisomerase I illustrates the potential of this approach.

AB - While the design of molecules that inhibit or antagonize the functions of specific macromolecules is now well precedented, in many cases the structural information requisite to the design process is lacking. The tools of molecular biology can now furnish the target macromolecules for use in mechanism-based exploration; highly defined assays can be devised based upon the known biochemistry of these macromolecules to permit the discovery of novel inhibitors or antagonists present in chemical collections. Presently, we describe a set of assays directed toward the discovery of novel inhibitors of eukaryotic topoisomerase I, an enzyme critical to maintenance of chromosomal DNA topology and therefore essential for normal replication and transcription. The identification of chebulagic acid as an extraordinarily potent and mechanistically novel inhibitor of topoisomerase I illustrates the potential of this approach.

UR - http://www.scopus.com/inward/record.url?scp=0026652785&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0026652785&partnerID=8YFLogxK

M3 - Article

VL - 55

SP - 401

EP - 413

JO - Journal of Natural Products

JF - Journal of Natural Products

SN - 0163-3864

IS - 4

ER -