Synthesis and structure–activity relationships of novel poly(ADP-ribose) polymerase-1 inhibitors

Tao, Ming; Park, Chung Ho; Bihovsky, Ron; Wells, Gregory J.; Husten, Jean; Ator, Mark A.; Hudkins, Robert L.

doi:10.1016/j.bmcl.2005.10.099

Cited by 46 publications

(23 citation statements)

References 25 publications

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“…Pyrrolocarbazole compounds A and B were prepared according to the concise approach in the literature29–31 (Scheme S.1, Supporting Information). In this sequence, in situ N -carboxylation of indole followed by directed lithiation at C2 and trapping with cyclopentanone provided the corresponding tertiary alcohol,35 which underwent dehydration upon treatment with hydrochloric acid.…”

Section: Resultsmentioning

confidence: 99%

“…Included are cervical (HeLa), testicular (NTera2), pancreatic (BxPC3) and osteosarcoma (U2OS) cells. Two previously reported PARP inhibitors were prepared according to literature protocols,29–31 and one step in the synthesis was improved. Photo-cross-linking experiments were preformed in the presence of one of these PARP inhibitors to determine its effect on the binding of nuclear proteins to platinum-damaged DNA.…”

Section: Introductionmentioning

confidence: 99%

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Poly(ADP-ribose) polymerase-1 activity facilitates the dissociation of nuclear proteins from platinum-modified DNA

Guggenheim

Ondrus

Movassaghi

et al. 2008

Bioorganic & Medicinal Chemistry

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The affinity of the poly(ADP-ribose) polymerase-1 (PARP-1) for platinum-damaged DNA was first discovered during photo-crosscroxss-linking experiments using the photoactive compound Pt-BP6 (Zhang, C. X.; Chang, P. V.; Lippard, S. J., J. Am. Chem. Soc. 2004, 126, 6536-6537), an analogue of the anticancer drug cis-diammine-dichloroplatinum(II), cisplatin. Although PARP inhibitors sensitize cancer cells to cisplatin, there are conflicting reports in the literature about their efficacy. In order to improve our understanding of the mechanism by which PARP inhibition might potentiate the cell-killing ability of cisplatin, and to shed light on the source of the discrepancy among different laboratories, we have in the present study probed the influence of three PARP inhibitors in four types of cancer cells, cervical (HeLa), testicular (NTera2), pancreatic (BxPC3) and osteosarcoma (U2OS), on the results of Pt-BP6 photo-cross-linking experiments and cytotoxicity assays. We find that the activity of PARP proteins following exposure to platinum-modified DNA results in the dissociation of DNA-bound proteins. PARP inhibitors were able to sensitize some, but not all, of the cell lines to cisplatin. This cell-line dependence and the potential consequences of PARP-initiated protein removal from platinum-DNA lesions are discussed. Control experiments revealed that NTera2 cells are especially sensitive to PARP inhibition.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Poly(ADP-ribose) polymerase-1 activity facilitates the dissociation of nuclear proteins from platinum-modified DNA

Guggenheim

Ondrus

Movassaghi

et al. 2008

Bioorganic & Medicinal Chemistry

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“…At the start of 2001, Cephalon filed patent applications describing a series of pyrrolo carbazole lactams as potent PARP inhibitors on the basis of high‐throughput screening . Lead‐optimization combined with determination of structure–activity relationships allowed researchers at Cephalon to improve the potency and solubility of the core structure of this series of compounds, leading to CEP–8983 ( 4 ), a high potency and moderately soluble PARP inhibitor ( K i = 20 n m ) . The issue of solubility was next solved by designing a soluble pro‐drug of the inhibitor (CEP–9722) ( 5 ).…”

Section: Parp Inhibitors In Clinical Trialsmentioning

confidence: 99%

PARP inhibitors: polypharmacology versus selective inhibition

et al. 2013

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Inhibition of ADP-ribosyltransferases with diphtheria toxin homology (ARTD), widely known as the poly(ADP-ribose) polymerase (PARP) family, is a strategy under development for treatment of various conditions, including cancers and ischemia. Here, we give a brief summary of ARTD enzyme functions and the implications for their potential as therapeutic targets. We present an overview of the PARP inhibitors that have been used in clinical trials. Finally, we summarize recent insights from structural biology, and discuss the molecular aspects of PARP inhibitors in terms of broad-range versus selective inhibition of ARTD family enzymes.

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“…Previously, our laboratories reported the identification of a novel pyrrolocarbazole compound 1 , as a potent PARP‐1 inhibitor (Figure , IC 50 36 n m ) from screening of our corporate chemical library . Although compound 1 displayed potency, its poor drug‐like characteristics, especially its extremely low solubility in various acceptable vehicles, made it difficult to perform in vivo experiments.…”

Section: Methodsmentioning

confidence: 99%