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- Aydin, Juhanes, et al.
(författare)
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Synthesis and catalytic application of chiral 1,1'-Bi-2-naphthol- and biphenanthrol-based pincer complexes: selective allylation of sulfonimines with allyl stannane and allyl trifluoroborate.
- 2007
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 72:13, s. 4689-4697
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Tidskriftsartikel (refereegranskat)abstract
- New easily accessible 1,1'-bi-2-naphthol- (BINOL-) and biphenanthrol-based chiral pincer complex catalysts were prepared for selective (up to 85% enantiomeric excess) allylation of sulfonimines. The chiral pincer complexes were prepared by a flexible modular approach allowing an efficient tuning of the selectivity of the catalysts. By employment of the different enantiomeric forms of the catalysts, both enantiomers of the homoallylic amines could be selectively obtained. Both allyl stannanes and allyl trifluoroborates can be employed as allyl sources in the reactions. The biphenanthrol-based complexes gave higher selectivity than the substituted BINOL-based analogues, probably because of the well-shaped chiral pocket generated by employment of the biphenanthrol complexes. The enantioselective allylation of sulfonimines presented in this study has important implications for the mechanism given for the pincer complex-catalyzed allylation reactions, confirming that this process takes place without involvement of palladium(0) species.
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- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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- Luttens, Andreas, et al.
(författare)
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Virtual Fragment Screening for DNA Repair Inhibitors in Vast Chemical Space
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Fragment-based screening can catalyze drug discovery by identifying novel scaffolds, but this approach is limited by the small chemical libraries studied by biophysical experiments and the challenging hit optimization step. In efforts to identify DNA repair inhibitors, we explored the use of structure-based virtual screening to access ultralarge fragment libraries that cover four orders of magnitude larger fractions of chemical space than traditional techniques. A set of 14 million fragments were docked to 8-oxoguanine DNA glycosylase (OGG1), a challenging drug target involved in cancer and inflammation. Of the 29 top-ranked fragments that were experimentally evaluated, four compounds were shown to bind to OGG1 and X-ray crystallography confirmed the predicted binding modes. Docking of readily synthesizable elaborations guided fragment optimization, leading to the discovery of submicromolar OGG1 inhibitors with anti-inflammatory and anti-cancer effects in cell models. Our results demonstrate that fragment-based virtual screening enables efficient exploration of vast chemical libraries.
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- Michel, Maurice, et al.
(författare)
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Computational and Experimental Druggability Assessment of Human DNA Glycosylases
- 2019
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 4:7, s. 11642-11656
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Tidskriftsartikel (refereegranskat)abstract
- Due to a polar or even charged binding interface, DNA-binding proteins are considered extraordinarily difficult targets for development of small-molecule ligands and only a handful of proteins have been targeted successfully to date. Recently, however, it has been shown that development of selective and efficient inhibitors of 8-oxoguanine DNA glycosylase is possible. Here, we describe the initial druggability assessment of DNA glycosylases in a computational setting and experimentally investigate several methods to target endonuclease VIII-like 1 (NEIL1) with small-molecule inhibitors. We find that DNA glycosylases exhibit good predicted druggability in both DNA-bound and -unbound states. Furthermore, we find catalytic sites to be highly flexible, allowing for a range of interactions and binding partners. One flexible catalytic site was rationalized for NEIL1 and further investigated experimentally using both a biochemical assay in the presence of DNA and a thermal shift assay in the absence of DNA.
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- Odell, Luke R., et al.
(författare)
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Synthesis of Substituted Indazole Acetic Acids by N-N Bond Forming Reactions
- 2023
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Ingår i: European Journal of Organic Chemistry. - : Wiley-Blackwell. - 1434-193X .- 1099-0690. ; 26:29
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Tidskriftsartikel (refereegranskat)abstract
- Herein, we report on the discovery and development of novel cascade N-N bond forming reactions for the synthesis of rare indazole acetic acid scaffolds. This approach allows for convenient synthesis of three distinct indazole acetic acid derivatives (unsubstituted, hydroxy, and alkoxy) by heating 3-amino-3-(2-nitroaryl)propanoic acids with an appropriate nucleophile/solvent under basic conditions. The reaction tolerates a range of functional groups and electronic effects and, in total, 23 novel indazole acetic acids were synthesized and characterized. This work offers a valuable strategy for the synthesis of useful scaffolds for drug discovery programs.
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