Details
| Original language | English |
|---|---|
| Pages (from-to) | 5450-5488 |
| Number of pages | 39 |
| Journal | Angewandte Chemie - International Edition |
| Volume | 52 |
| Issue number | 21 |
| Publication status | Published - 17 May 2013 |
Abstract
Shortly after the discovery of the proteasome it was proposed that inhibitors could stabilize proteins which ultimately would trigger apoptosis in tumor cells. The essential questions were whether small molecules would be able to inhibit the proteasome without generating prohibitive side effects and how one would derive these compounds. Fortunately, "Mother Nature" has generated a wide variety of natural products that provide distinct selectivities and specificities. The chemical synthesis of these natural products finally provided access to analogues and optimized drugs of which two different classes have been approved for the treatment of malignancies. Despite these achievements, additional lead structures derived from nature are under investigation and will be discussed with regard to their biological potential and chemical challenges. The ubiquitin-proteasome system controls fundamental processes such as cell cycle regulation, DNA repair, apoptosis, and immune and inflammatory responses, as well as hereditary disorders such as cystic fibrosis. This Review covers the synthesis of the most important proteasome inhibitors as well as their mode of action and clinical development.
Keywords
- antitumor agents, clinical development, inhibitors, natural products, proteasome
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
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In: Angewandte Chemie - International Edition, Vol. 52, No. 21, 17.05.2013, p. 5450-5488.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Synthesis and pharmacology of proteasome inhibitors
AU - Rentsch, Andreas
AU - Landsberg, Dirk
AU - Brodmann, Tobias
AU - Bülow, Leila
AU - Girbig, Anna Katharina
AU - Kalesse, Markus
PY - 2013/5/17
Y1 - 2013/5/17
N2 - Shortly after the discovery of the proteasome it was proposed that inhibitors could stabilize proteins which ultimately would trigger apoptosis in tumor cells. The essential questions were whether small molecules would be able to inhibit the proteasome without generating prohibitive side effects and how one would derive these compounds. Fortunately, "Mother Nature" has generated a wide variety of natural products that provide distinct selectivities and specificities. The chemical synthesis of these natural products finally provided access to analogues and optimized drugs of which two different classes have been approved for the treatment of malignancies. Despite these achievements, additional lead structures derived from nature are under investigation and will be discussed with regard to their biological potential and chemical challenges. The ubiquitin-proteasome system controls fundamental processes such as cell cycle regulation, DNA repair, apoptosis, and immune and inflammatory responses, as well as hereditary disorders such as cystic fibrosis. This Review covers the synthesis of the most important proteasome inhibitors as well as their mode of action and clinical development.
AB - Shortly after the discovery of the proteasome it was proposed that inhibitors could stabilize proteins which ultimately would trigger apoptosis in tumor cells. The essential questions were whether small molecules would be able to inhibit the proteasome without generating prohibitive side effects and how one would derive these compounds. Fortunately, "Mother Nature" has generated a wide variety of natural products that provide distinct selectivities and specificities. The chemical synthesis of these natural products finally provided access to analogues and optimized drugs of which two different classes have been approved for the treatment of malignancies. Despite these achievements, additional lead structures derived from nature are under investigation and will be discussed with regard to their biological potential and chemical challenges. The ubiquitin-proteasome system controls fundamental processes such as cell cycle regulation, DNA repair, apoptosis, and immune and inflammatory responses, as well as hereditary disorders such as cystic fibrosis. This Review covers the synthesis of the most important proteasome inhibitors as well as their mode of action and clinical development.
KW - antitumor agents
KW - clinical development
KW - inhibitors
KW - natural products
KW - proteasome
UR - http://www.scopus.com/inward/record.url?scp=84877721642&partnerID=8YFLogxK
U2 - 10.1002/anie.201207900
DO - 10.1002/anie.201207900
M3 - Article
C2 - 23526565
AN - SCOPUS:84877721642
VL - 52
SP - 5450
EP - 5488
JO - Angewandte Chemie - International Edition
JF - Angewandte Chemie - International Edition
SN - 1433-7851
IS - 21
ER -