For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
10
views
40
references
 Top references
cited by
6
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      450
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Design of indole- and MCR-based macrocycles as p53-MDM2 antagonists

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Macrocycles were designed to antagonize the protein–protein interaction p53-MDM2 based on the three-finger pharmacophore F 19W 23L 25. The synthesis was accomplished by a rapid, one-pot synthesis of indole-based macrocycles based on Ugi macrocyclization. The reaction of 12 different α,ω-amino acids and different indole-3-carboxaldehyde derivatives afforded a unique library of macrocycles otherwise difficult to access. Screening of the library for p53-MDM2 inhibition by fluorescence polarization and 1H, 15N HSQC NMR measurements confirm MDM2 binding.

          Related collections

          Most cited references40

          • Record: found
          • Abstract: found
          • Article: not found

          Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.

          Duncan Scott, Andrew Bayly, Chris Abell … (2016)
          Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.
          Article 0 comments Cited 299 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Awakening guardian angels: drugging the p53 pathway.

            Christopher Brown, Sonia Lain, Chandra Verma … (2009)
            Currently, around 11 million people are living with a tumour that contains an inactivating mutation of TP53 (the human gene that encodes p53) and another 11 million have tumours in which the p53 pathway is partially abrogated through the inactivation of other signalling or effector components. The p53 pathway is therefore a prime target for new cancer drug development, and several original approaches to drug discovery that could have wide applications to drug development are being used. In one approach, molecules that activate p53 by blocking protein-protein interactions with MDM2 are in early clinical development. Remarkable progress has also been made in the development of p53-binding molecules that can rescue the function of certain p53 mutants. Finally, cell-based assays are being used to discover compounds that exploit the p53 pathway by either seeking targets and compounds that show synthetic lethality with TP53 mutations or by looking for non-genotoxic activators of the p53 response.
            Article 0 comments Cited 266 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Contemporary strategies for peptide macrocyclization.

              Christopher White, Andrei Yudin (2011)
              Peptide macrocycles have found applications that range from drug discovery to nanomaterials. These ring-shaped molecules have shown remarkable capacity for functional fine-tuning. Such capacity is enabled by the possibility of adjusting the peptide conformation using the techniques of chemical synthesis. Cyclic peptides have been difficult, and often impossible, to prepare using traditional synthetic methods. For macrocyclization to occur, the activated peptide must adopt an entropically disfavoured pre-cyclization conformation before forming the desired product. Here, we review recent solutions to some of the major challenges in this important area of contemporary synthesis.
              Article 0 comments Cited 207 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Contributors
                Alexander Dömling
                Thomas J J Müller: Role: Guest Editor
                Journal
                Journal ID (nlm-ta): Beilstein J Org Chem
                Journal ID (iso-abbrev): Beilstein J Org Chem
                Title: Beilstein Journal of Organic Chemistry
                Publisher: Beilstein-Institut (Trakehner Str. 7-9, 60487 Frankfurt am Main, Germany )
                ISSN (Electronic): 1860-5397
                Publication date Collection: 2019
                Publication date (Electronic): 20 February 2019
                Volume: 15
                Pages: 513-520
                Affiliations
                [1 ]Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9700 AD Groningen, The Netherlands
                [2 ]Chemistry Department, Tarbiat Modares University, P.O. Box 14155-4838, Tehran, Iran
                [3 ]Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Krakow, Poland
                Author information
                http://orcid.org/0000-0001-5098-5504
                http://orcid.org/0000-0003-4834-1990
                http://orcid.org/0000-0002-9008-2729
                http://orcid.org/0000-0002-4103-4675
                http://orcid.org/0000-0001-9369-6024
                Article
                DOI: 10.3762/bjoc.15.45
                PMC ID: 6404402
                SO-VID: 845b9237-13d2-4509-bdc9-ecc87aadd337
                Copyright © Copyright © 2019, Neochoritis et al.; licensee Beilstein-Institut.
                License:

                This is an Open Access article under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0). Please note that the reuse, redistribution and reproduction in particular requires that the authors and source are credited.

                The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (https://www.beilstein-journals.org/bjoc)

                History
                Date received : 25 October 2018
                Date accepted : 14 February 2019
                Categories
                Subject: Full Research Paper
                Subject: Chemistry
                Subject: Organic Chemistry

                ScienceOpen disciplines: Organic & Biomolecular chemistry
                Keywords: 1h,15n hsqc nmr,indole,macrocycles,multicomponent,p53-mdm2,ugi reaction
                Data availability:
                ScienceOpen disciplines: Organic & Biomolecular chemistry
                Keywords: 1h,15n hsqc nmr, indole, macrocycles, multicomponent, p53-mdm2, ugi reaction

                Comments

                Comment on this article

                scite_

                Similar content450

                See all similar

                Cited by5

                See all cited by

                Most referenced authors522

                See all reference authors