Design, Synthesis, and Evaluation of 3,4-Dihydro-2<i>H</i>-[1,4]diazepino[6,7,1-<i>hi</i>]indol-1-ones as Inhibitors of Poly(ADP-Ribose) Polymerase

Tikhe, Jayashree; Webber, S. E.; Hostomský, Zdeněk; Maegley, Karen A.; Ekkers, Anne; Li, Jianke; Yu, Xin; Almassy, Robert J.; Kumpf, Robert A.; Boritzki, Theodore J.; Zhang, Cathy; Calabrese, Chris R.; Curtin, Nicola J.; Kyle, Suzanne; Thomas, Huw D.; Wang, Lan-Zhen; Calvert, A. Hilary; Golding, Bernard T.; Griffin, Roger J.; Newell, David R.

doi:10.1021/jm030513r

Cited by 45 publications

(22 citation statements)

References 42 publications

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“…A second test of the Fukui grid score was to rank a set of known binders for poly ADP-ribose polymerase (PDB:1EFY) taken from the DUD database 54,55. The ligands are all similar in structure, with substitutions made at both the R 1 and R 2 positions of the molecular scaffold shown in Figure 7a.…”

Section: General Computational Detailsmentioning

confidence: 99%

Utility of the Hard/Soft Acid−Base Principle via the Fukui Function in Biological Systems

Faver

Merz

2010

J. Chem. Theory Comput.

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The hard/soft acid-base principle has long been known to be an excellent predictor of chemical reactivity. The Fukui function, a reactivity descriptor from conceptual density functional theory, has been shown to be related to the local softness of a system. The usefulness of the Fukui function is explored and demonstrated herein for three common biological problems: ligand docking, active site detection, and protein folding. In each type of study, a scoring function is developed based on the local HSAB principle using atomic Fukui indices. Even with necessary approximations for its use in large systems, the Fukui function remains a useful descriptor for predicting chemical reactivity and understanding chemical systems.

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Section: General Computational Detailsmentioning

confidence: 99%

Utility of the Hard/Soft Acid−Base Principle via the Fukui Function in Biological Systems

Faver

Merz

2010

J. Chem. Theory Comput.

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“…A data set (Tikhe et al, 2004) comprising 41 analogs of indole-1-ones was selected for the present investigations. The basic structures of these analogs are depicted in Fig.…”

Section: Model Development Analysismentioning

confidence: 99%

“…Suitable models were developed after identification of the active ranges. Subsequently, each analog was assigned a biological activity using this model, which was then compared with the reported (Tikhe et al, 2004) poly(ADP-ribose) polymerase inhibitory activity. The poly(ADP-ribose) polymerase inhibitory activity was reported quantitatively as K i values at different concentrations.…”

Section: Model Development Analysismentioning

confidence: 99%

Topochemical models for the prediction of poly(ADP-ribose) polymerase inhibitory activity of indole-1-ones

Dureja

Мадан

2007

Med Chem Res

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The relationship between the topochemical indices and poly(ADP-ribose) polymerase inhibitory activity of indole-1-ones has been investigated. Wiener's topochemical index, a distance-based topochemical descriptor; molecular connectivity topochemical index, an adjacency-based topochemical descriptor; and superadjacency topochemical index, an adjacency-cum-distance-based topochemical descriptor, were used for the present investigation. The values of Wiener's topochemical index, molecular connectivity topochemical index, and superadjacency topochemical index for each of 41 analogs comprising the data set were computed via an in-house computer program. Resulting data were analyzed and suitable models were developed after identification of the active ranges. Subsequently, a biological activity was assigned to each analog involved in the data set using these models, which was then compared with the reported poly(ADP-ribose) polymerase inhibitory activity. Statistical analysis revealed that two of the three models were not intercorrelated. Accuracy of prediction of these models varied from approximately 83% to 85%.

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“…18) were based around the structure of nicotamide, a by-product of the poly(ADP-ribosylation) reaction and a weak PARP inhibitor in itself. Purifi cation of chicken PARP allowed X-ray crystallography of the NAD + binding site (19) leading to the identifi cation of structure activity relationships and the development of more potent inhibitors (20)(21)(22)(23)(24). It is these agents that have entered early clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Targeting Poly(ADP-Ribose) Polymerase: A Two-Armed Strategy for Cancer Therapy

Plummer¹,

Calvert²

2008

AACR Education book

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Th e DNA repair pathways are protective of the host genome in normal cells; however, in cancer cells, these pathways may be disrupted and predispose to tumorigenesis or their activity may overcome the potentially cytotoxic damage caused by anticancer agents and be a mechanism of resistance. Poly(ADP-ribose) polymerase inhibitors, which block base excision repair of single-strand breaks, have entered the clinic in the last few years. Th is article discusses the interactions between the pathways of single-and double-strand break repair, which explain the two clinical development strategies for this class of drugs.

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Design, Synthesis, and Evaluation of 3,4-Dihydro-2H-[1,4]diazepino[6,7,1-hi]indol-1-ones as Inhibitors of Poly(ADP-Ribose) Polymerase

Cited by 45 publications

References 42 publications

Utility of the Hard/Soft Acid−Base Principle via the Fukui Function in Biological Systems

Utility of the Hard/Soft Acid−Base Principle via the Fukui Function in Biological Systems

Topochemical models for the prediction of poly(ADP-ribose) polymerase inhibitory activity of indole-1-ones

Targeting Poly(ADP-Ribose) Polymerase: A Two-Armed Strategy for Cancer Therapy

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