Novel 5-azaindolocarbazoles as cytotoxic agents and Chk1 inhibitors

Lefoix, Myriam; Coudert, G.; Routier, Sylvain; Pfeiffer, Bruno; Caignard, Daniel‐Henri; Hickman, John A.; Pierre, Alain St.; Golsteyn, Roy M.; Léonce, Stéphane; Bossard, Céline; Mérour, Jean‐Yves

doi:10.1016/j.bmc.2008.02.086

Cited by 28 publications

(27 citation statements)

References 54 publications

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“…The 10-hydroxyanalogue (14) showed the best inhibitory activity and was half as cytotoxic (IC 50 =14 nM) as UCN-01 (7 nM). 16 (Fig. 12).…”

Section: Checkpoint Inhibitors (Chkis)mentioning

confidence: 91%

“…The enzyme is partly flexible in its inactive form but has a stable conformation upon binding of substrates or inhibitors. The nucleotide-binding pocket lies in the glycine rich loop (residues [16][17][18][19][20][21][22][23] in the N-terminal domain, while the activation loop (amino acids 148-175) is located in the C-terminus and is stable in the apoenzyme. 11 Roughly 80 percent of the secondary structure of CdK2 is similar to that of Chk1.…”

Section: Checkpoint Inhibitors (Chkis)mentioning

confidence: 99%

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Natural Products from Terrestrial Microbial Organisms with Cytotoxic Cell Cycle Inhibitors

Dreis¹,

Gartner²,

Krebs³

et al. 2014

Biodiversity, Natural Products and Cancer Treatment

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Many microbial products have the potential for therapeutic application, e.g. as anticancer drugs. This chapter presents natural products from terrestrial microbial organisms that attack various targets in tumor cells, e.g. cell cycle inhibitors (inhibitors of phosphoinositide-3-kinase, checkpoint kinase inhibitors, inhibitors of dual specificity phosphatases, inhibitors of cyclin-dependent kinases), inhibitors of histone deacetylases, topoisomerases, or growth factors as well as inhibitors of the proteasome, of heat shock protein 90, nuclear trafficking, or ATPase.New cancer drugs are most likely be used as part of combination therapy regimens. Attacking different targets in tumor cells may kill tumor cells resistant to one target. The potential of novel target-directed compounds to eradicate otherwise drug-resistant cells is an attractive perspective, which deserves further investigation.

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“…The 10-hydroxyanalogue (14) showed the best inhibitory activity and was half as cytotoxic (IC 50 =14 nM) as UCN-01 (7 nM). 16 (Fig. 12).…”

Section: Checkpoint Inhibitors (Chkis)mentioning

confidence: 91%

Section: Checkpoint Inhibitors (Chkis)mentioning

confidence: 99%

Natural Products from Terrestrial Microbial Organisms with Cytotoxic Cell Cycle Inhibitors

Dreis¹,

Gartner²,

Krebs³

et al. 2014

Biodiversity, Natural Products and Cancer Treatment

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“…For the pharmacophore modeling algorithm adopted here, the requirements for the training set compounds include: (1) Ͼϭ15 compounds necessary to assure statistical power; (2) activity should span at least 4 orders of magnitude; (3) each order of magnitude represented by Ͼϭ3 compounds; (4) compounds with similar structures should differ in activity by at least one order of magnitude; and (5) compounds with similar activity must be structurally distinct. According to these criteria, we carefully chose twenty-two Chk1 inhibitors, which were collected from different literature resources, [22][23][24][25][26][27][28][29][30][31][32] to form a training set for the generation of quantitative pharmacophore models. Their IC 50 (half maximal inhibitory concentration) values span a range of 6 orders of magnitude (from 0.5 to 31800 nM).…”

Section: Methodsmentioning

confidence: 99%

Pharmacophore Modeling and Virtual Screening Studies of Checkpoint Kinase 1 Inhibitors

Chen

Liu

Yang

et al. 2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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Checkpoint kinase 1 (Chk1), a serine/threonine kinase, plays a critical role in the regulation of the cell-cycle G2/M checkpoint.1-3) When DNA damage is detected in human cells, as a response, Chk1 is activated through ATM/ATR pathway. The activated Chk1 triggers the G2/M checkpoint, which arrests the cells in G2 to allow time for repairing their DNA. The inhibition of Chk1 kinase has been shown to result in abrogation of the G2/M checkpoint, which would permit premature mitotic entry in the presence of DNA damage, leading ultimately to cell death. [4][5][6] This suggests a potential therapeutic use of Chk1 inhibitors in cancer therapy; that is as sensitizing agents of DNA damaging drugs which are still a major component of cancer therapy.3,7-9) Indeed, several Chk1 inhibitors, including UCN-01 10) and SB-218078, 2,11) have been reported to be able to enhance the cytotoxicities of the standard DNA-damaging agents in vivo. In addition, selective Chk1 inhibitors are also helpful in the study of G2/M checkpoint signaling. 3,12) Therefore, development of Chk1 inhibitors has attracted much attention in recent years.Currently, many academic institutes and pharmaceutical companies have been involved in the development of Chk1 inhibitors. And a considerable number of compounds have been reported to have inhibitory potency against Chk1. Some compounds, such as PF-477736, AZD7762 and UCN-01, 9,12,13) have entered into clinical trials. Even so, discovering more potent Chk1 inhibitors with novel chemical structures are still needed and important in order to provide more lead candidates for the drug development.Quantitative structure-activity relationship (QSAR) methods, particularly three dimensional QSAR (3D-QSAR), have been demonstrated as an effective tool in discovering novel lead compounds.14,15) And pharmacophore modeling method is one of the best 3D-QSAR methods, which has been successfully applied to the drug discovery. [16][17][18][19][20] Thus, in this investigation, we shall first develop 3D pharmacophore models of Chk1 inhibitors based on the known Chk1 inhibitors. It is expected that the established pharmacophore models are able to correctly elucidate the QSAR of the Chk1 inhibitors. Then the best pharmacophore model obtained will be used to screen chemical libraries to identify new inhibitors against Chk1. ExperimentalPharmacophore Modeling All the pharmacophore modeling calculations were carried out by using CATALYST 4.11 software package (Accelrys, San Diego, U.S.A.).21) The common pharmacophore features necessary for potent Chk1 inhibitors were identified by HipHop program, and quantitative pharmacophore models were created by HypoRefine module within CATALYST.In pharmacophore modeling, the selection of training set compounds is critical to the quality of produced models. Each modeling algorithm has its own requirements that should be conformed to, particularly in the aspects of chemical structural diversity and bioactivity variation of the training set compounds. For the pharmacophore modeling algorithm ad...

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“…[1][2][3] However, the synthesis of azaindoles has remained a challenge for synthetic chemists both in academia and in the pharmaceutical industry because the classic methods for the synthesis of indole derivatives and related N-containing heterocycles do not work well in the synthesis of azaindole analogues, or at least, they work but not efficiently. [1][2][3][4][5] In recent years, strategies applying organometallic chemistry, particularly transition-metal-mediated or -catalysed reactions and lithiation approaches, have greatly contributed to the development of azaindole synthesis and azaindole chemistry.…”

Section: Introductionmentioning

confidence: 99%

One‐Pot Multicomponent Synthesis of Azaindoles and Pyrroles from One Molecule of a Silicon‐Tethered Diyne and Three or Two Molecules of Organonitriles Mediated by Zirconocene

Zhang

Sun

Zhang

et al. 2009

Chemistry A European J

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A zirconocene-mediated one-pot multicomponent synthesis process leading to the synthesis of pyrrolo[3,2-c]pyridine (5-azaindoles) and pyrrole derivatives has been developed starting from a silicon-tethered diyne and three or two different or identical organonitriles. Pyrrolo[3,2-c]pyridine and pyrrole derivatives with diverse structures and substitution patterns have been highly selectively prepared by this protocol. A wide variety of organonitriles and silicon-tethered diynes, either aliphatic or aromatic with both electron-withdrawing and -donating groups, have been used to afford 5-azaindoles and/or pyrroles in good-to-excellent isolated yields. A key intermediate formed in the Cp(2)Zr(II)-mediated reaction of one (PhC[triple bond]C)(2)SiMe(2), two molecules of iPrCN and one p-tolylCN was characterised by X-ray single-crystal structural analysis, which has allowed us to gain a good understanding of the reaction process.

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Novel 5-azaindolocarbazoles as cytotoxic agents and Chk1 inhibitors

Cited by 28 publications

References 54 publications

Natural Products from Terrestrial Microbial Organisms with Cytotoxic Cell Cycle Inhibitors

Natural Products from Terrestrial Microbial Organisms with Cytotoxic Cell Cycle Inhibitors

Pharmacophore Modeling and Virtual Screening Studies of Checkpoint Kinase 1 Inhibitors

One‐Pot Multicomponent Synthesis of Azaindoles and Pyrroles from One Molecule of a Silicon‐Tethered Diyne and Three or Two Molecules of Organonitriles Mediated by Zirconocene

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