On the binding of indeno[1,2-c]isoquinolines in the DNA-topoisomerase I cleavage complex

Xiangshu Xiao, Smitha Antony, Yves Pommier, Mark Cushman

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

An ab initio quantum mechanics calculation is reported which predicts the orientation of indenoisoquinoline 4 in the ternary cleavage complex formed from DNA and topoisomerase I (top1). The results of this calculation are consistent with the hypothetical structures previously proposed for the indenoisoquinoline-DNA-topi ternary complexes based on molecular modeling, the crystal structure of a recently reported ternary complex, and the biological results obtained with a pair of diaminoalkyl-substituted indenoisoquinoline enantiomers. The results of these studies indicate that the π-π stacking interactions between the indenoisoquinolines and the neighboring DNA base pairs play a major role in determining binding orientation. The calculation of the electrostatic potential surface maps of the indenoisoquinolines and the adjacent DNA base pairs shows electrostatic complementarity in the observed binding orientation, leading to the conclusion that electrostatic attraction between the intercalators and the base pairs in the cleavage complex plays a major stabilizing role. On the other hand, the calculation of LUMO and HOMO energies of indenoisoquinoline 13b and neighboring DNA base pairs in conjunction with NBO analysis indicates that charge transfer complex formation plays a relatively minor role in stabilizing the ternary complexes derived from indenoisoquinolines, DNA, and top1. The results of these studies are important in understanding the existing structure-activity relationships for the indenoisoquinolines as topi inhibitors and as anticancer agents, and they will be important in the future design of indenoisoquinoline-based top1 inhibitors.

Original languageEnglish (US)
Pages (from-to)3231-3238
Number of pages8
JournalJournal of Medicinal Chemistry
Volume48
Issue number9
DOIs
StatePublished - May 5 2005
Externally publishedYes

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Isoquinolines
Type I DNA Topoisomerase
Base Pairing
Static Electricity
DNA
Electrostatics
Intercalating Agents
Molecular modeling
Enantiomers
Quantum theory
Structure-Activity Relationship
Mechanics
Antineoplastic Agents
Charge transfer
Crystal structure

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

On the binding of indeno[1,2-c]isoquinolines in the DNA-topoisomerase I cleavage complex. / Xiao, Xiangshu; Antony, Smitha; Pommier, Yves; Cushman, Mark.

In: Journal of Medicinal Chemistry, Vol. 48, No. 9, 05.05.2005, p. 3231-3238.

Research output: Contribution to journalArticle

Xiao, Xiangshu ; Antony, Smitha ; Pommier, Yves ; Cushman, Mark. / On the binding of indeno[1,2-c]isoquinolines in the DNA-topoisomerase I cleavage complex. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 9. pp. 3231-3238.
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abstract = "An ab initio quantum mechanics calculation is reported which predicts the orientation of indenoisoquinoline 4 in the ternary cleavage complex formed from DNA and topoisomerase I (top1). The results of this calculation are consistent with the hypothetical structures previously proposed for the indenoisoquinoline-DNA-topi ternary complexes based on molecular modeling, the crystal structure of a recently reported ternary complex, and the biological results obtained with a pair of diaminoalkyl-substituted indenoisoquinoline enantiomers. The results of these studies indicate that the π-π stacking interactions between the indenoisoquinolines and the neighboring DNA base pairs play a major role in determining binding orientation. The calculation of the electrostatic potential surface maps of the indenoisoquinolines and the adjacent DNA base pairs shows electrostatic complementarity in the observed binding orientation, leading to the conclusion that electrostatic attraction between the intercalators and the base pairs in the cleavage complex plays a major stabilizing role. On the other hand, the calculation of LUMO and HOMO energies of indenoisoquinoline 13b and neighboring DNA base pairs in conjunction with NBO analysis indicates that charge transfer complex formation plays a relatively minor role in stabilizing the ternary complexes derived from indenoisoquinolines, DNA, and top1. The results of these studies are important in understanding the existing structure-activity relationships for the indenoisoquinolines as topi inhibitors and as anticancer agents, and they will be important in the future design of indenoisoquinoline-based top1 inhibitors.",
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