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Cited by 49Cancer-related Molecular PathwaysFluorine in Organic ChemistrySynthesis and Characterization of Heterocyclic Compounds

Exhaustive Fluorine Scanning toward Potent p53–Mdm2 Antagonists

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Huang, Yijun, Wolf, Siglinde, Koes, David, Popowicz, Grzegorz M., Camacho, Carlos J., Holak, Tad A., Dömling, Alexander·2012·ChemMedChem
DOI 10.1002/cmdc.201100428PMC PMC3772510
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Abstract

Fluorine dance: We discovered potent p53–Mdm2 antagonists by systematically varying the fluorine substitution pattern around a benzyl group that undergoes stacking interactions with His 96 of Mdm2. The potency of the optimized enantiomer (S)-7 e is >50-fold better than the worst compound of the series. All compounds were efficiently synthesized by Ugi multicomponent reaction chemistry.

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References 39 · Cited by 49

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  1. [2]Shimizu M Hiyama T Angew. Chem. Int. Ed 2005 44 214 231 15614922
  2. [3](a) Müller K Faeh C Diederich F Science 2007 317 1881 1886 17901324 (b) Salonen LM Ellermann M Diederich F Angew. Chem. Int. Ed 2011 50 4808 4842 21538733
  3. [4]Böhm H-J Banner D Bendels S Kansy M Kuhn B Müller K Obst-Sander U Stahl M Chem Bio Chem 2004 5 637 643 15122635
  4. [5]Hagmann WK J. Med. Chem 2008 51 4359 4369 18570365
  5. [6]Purser S Moore PR Swallow S Gouverneur V Chem. Soc. Rev 2008 37 320 330 18197348
  6. [7]Backes BJ Longenecker K Hamilton GL Stewart K Lai C Kopecka H von Geldern TW Madar DJ Pei Z Lubben TH Zinker BA Tian Z Ballaron SJ Stashko MA Mika AK Beno DWA Kempf-Grote AJ Black-Schaefer C Sham HL Trevillyan JM Bioorg. Med. Chem. Lett 2007 17 2005 2012 17276063
  7. [8]Morgenthaler M Schweizer E Hoffmann-Röder A Benini F Martin RE Jaeschke G Wagner B Fischer H Bendels S Zimmerli D Schneider J Diederich F Kansy M Müller K Chem Med Chem 2007 2 1100 1115 17530727
  8. [9]Su H Xie Y Liu W-B You S-L Bioorg. Med. Chem. Lett 2011 21 3578 3582 21602044
  9. [10]Kerekes AD Esposite SJ Doll RJ Tagat JR Yu T Xiao Y Zhang Y Prelusky DB Tevar S Gray K Terracina GA Lee S Jones J Liu M Basso AD Smith EB J. Med. Chem 2011 54 201 210 21128646
  10. [11]Park BK Kitteringham NR O'Neill PM Ann. Rev. Pharm. Tox 2001 41 443 470 11264465
  11. [12]Percival A J. Antimicrob. Chemother 1991 28 1 8 1787126
  12. [15]Yanamala N Dutta A Beck B Van Fleet B Hay K Yazbak A Ishima R Dömling A Klein-Seetharaman J Chem. Biol. Drug Des 2010 75 237 256 20331645
  13. [16]Cheok CF Verma CS Baselga J Lane DP Nat. Rev. Clin. Oncol 2011 8 25 37 20975744
  14. [17]Khoury K Popowicz GM Holak TA Dömling A Med Chem Comm 2011 2 246 260 PMC3898590 24466404
  15. [18]Popowicz GM Dömling A Holak TA Angew. Chem. Int. Ed 2011 50 2680 2688 PMC3113661 21341346
  16. [19]Koes D Khoury K Huang Y Wang W Bista M Popowicz GM Wolf S Holak TA Dömling A Camacho CJ PLoS Compu. Biol in press PMC3299697 22427896
  17. [20]a) Czarna A Beck B Srivastava S Popowicz GM Wolf S Huang Y Bista M Holak TA Dömling A Angew. Chem. Int. Ed 2010 49 5352 5356 PMC3772515 20575124 b) Huang Y Wolf S Bista M Meireles L Camacho C Holak TA Dömling A Chem. Biol. Drug Des 2010 76 116 129 20492448 PMC2913441 c) Srivastava S Beck B Wang W Czarna A Holak TA Dömling A J. Comb. Chem 2009 11 631 639 19548636 PMC2891308
  18. [21]Popowicz GM Czarna A Wolf S Wang K Wang W Dömling A Holak TA Cell Cycle 2010 9 1104 1111 20237429
  19. [23]Dömling A Curr. Opin. Chem. Biol 2008 12 281 291 18501203
  20. [24]Ono T Kukhar VP Soloshonok VA J. Org. Chem 1996 61 6563 6569 11667521
  21. [25]Popowicz G Czarna A Holak T Cell Cycle 2008 7 2441 2443 18677113
  22. [26]Abad-Zapatero C Metz JT Drug Discov. Today 2005 10 464 469 15809192
  23. [28]a) Kim CY Chang JS Doyon JB Baird TT Fierke CA Jain A Christianson DW J. Am. Chem. Soc 2000 122 12125 12130 b) Kim CY Chandra PP Jain A Christianson DW J. Am. Chem. Soc 2001 123 9620 9627 11572683
  24. [29]Warren GL Andrews CW Capelli AM Clarke B LaLonde J Lambert MH Lindvall M Nevins N Semus SF Senger S Tedesco G Wall ID Woolven JM Peishoff CE Head MS J. Med. Chem 2006 49 5912 5931 17004707
  25. [30]Wlodek S Skillman AG Nicholls AJ Chem. Theory Comput 2010 6 2140 2152 26615941

Authors
Huang, Y., Wolf, S., Koes, D., Popowicz, G. M., Camacho, C. J., Holak, T. A., & Dömling, A.
Affiliations
  • University of Pittsburgh (US)
  • Max Planck Institute of Biochemistry (DE)
Corresponding author
Dömling, Alexander
ORCID
Venue
ChemMedChem
Publisher
Wiley
Published
2011-09-27
Volume
7
Issue
1
Pages
49-52
ISSN
  • 1860-7179 (ISSN-L)
  • 1860-7187
DOI
10.1002/cmdc.201100428
PMC
PMC3772510
OpenAlex
W2109102757
Cited by
49
References
39
Citations by year
2026: 1 · 2025: 1 · 2023: 2 · 2021: 3 · 2020: 6 · 2019: 2 · 2018: 6 · 2017: 3 · 2016: 2 · 2015: 5 · 2014: 7 · 2013: 4 · 2012: 7
FWCI
3.31
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • ChemMedChem (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DORA PSI (Paul Scherrer Institute) (submittedVersion)
  • Max Planck Institute for Plasma Physics (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of General Medical Sciences (R21GM087617, P41GM094055, R01GM097082)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Fluorine in Organic Chemistry
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and Characterization of Heterocyclic Compounds
Keywords
benzyl group, stacking interactions, Ugi reaction, small molecule inhibitors, p53
MeSH terms
Benzene Derivatives, Fluorine, Humans, Models, Molecular, Protein Binding, Tumor Suppressor Protein p53, Proto-Oncogene Proteins c-mdm2, Drug Discovery

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