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On the binding of indeno[1,2-c]isoquinolines in the DNA-topoisomerase I cleavage complex.
J Med Chem. 2005 May 05; 48(9):3231-8.JM

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-top1 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 pi-pi 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 top1 inhibitors and as anticancer agents, and they will be important in the future design of indenoisoquinoline-based top1 inhibitors.

Authors+Show Affiliations

Department of Medicinal Chemistry and Molecular Pharmacology and the Purdue Cancer Center, School of Pharmacy and Pharmaceutical Sciences, Purdue University, West Lafayette, Indiana 47907, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15857129

Citation

Xiao, Xiangshu, et al. "On the Binding of Indeno[1,2-c]isoquinolines in the DNA-topoisomerase I Cleavage Complex." Journal of Medicinal Chemistry, vol. 48, no. 9, 2005, pp. 3231-8.
Xiao X, Antony S, Pommier Y, et al. On the binding of indeno[1,2-c]isoquinolines in the DNA-topoisomerase I cleavage complex. J Med Chem. 2005;48(9):3231-8.
Xiao, X., Antony, S., Pommier, Y., & Cushman, M. (2005). On the binding of indeno[1,2-c]isoquinolines in the DNA-topoisomerase I cleavage complex. Journal of Medicinal Chemistry, 48(9), 3231-8.
Xiao X, et al. On the Binding of Indeno[1,2-c]isoquinolines in the DNA-topoisomerase I Cleavage Complex. J Med Chem. 2005 May 5;48(9):3231-8. PubMed PMID: 15857129.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - On the binding of indeno[1,2-c]isoquinolines in the DNA-topoisomerase I cleavage complex. AU - Xiao,Xiangshu, AU - Antony,Smitha, AU - Pommier,Yves, AU - Cushman,Mark, PY - 2005/4/29/pubmed PY - 2005/6/4/medline PY - 2005/4/29/entrez SP - 3231 EP - 8 JF - Journal of medicinal chemistry JO - J Med Chem VL - 48 IS - 9 N2 - 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-top1 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 pi-pi 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 top1 inhibitors and as anticancer agents, and they will be important in the future design of indenoisoquinoline-based top1 inhibitors. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/15857129/On_the_binding_of_indeno[12_c]isoquinolines_in_the_DNA_topoisomerase_I_cleavage_complex_ DB - PRIME DP - Unbound Medicine ER -