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Oligonucleotide transition state analogues of saporin L3.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2017 Feb 15; Vol. 127, pp. 793-809. Date of Electronic Publication: 2016 Oct 27. - Publication Year :
- 2017
-
Abstract
- Ribosome inactivating proteins (RIPs) are among the most toxic agents known. More than a dozen clinical trials against refractory cancers have been initiated using modified RIPs with impressive results. However, dose-limiting toxicity due to vascular leak syndrome limits success of the therapy. We have previously reported some tight-binding transition state analogues of Saporin L3 that mimic small oligonucleotide substrates in which the susceptible adenosine has been replaced by a 9-deazaadenyl hydroxypyrrolidinol derivative. They provide the first step in the development of rescue agents to prevent Saporin L3 toxicity on non-targeted cells. Here we report the synthesis, using solution phase chemistry, of these and a larger group of transition state analogues. They were tested for inhibition against Saporin L3 giving K <subscript>i</subscript> values as low as 3.3 nM and indicating the structural requirements for inhibition.<br /> (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Base Sequence
Models, Molecular
Oligonucleotides genetics
Protein Conformation
RNA genetics
RNA metabolism
Ribosome Inactivating Proteins, Type 1 metabolism
Ribosome Inactivating Proteins, Type 1 toxicity
Saporins
Biomimetic Materials chemistry
Biomimetic Materials pharmacology
Oligonucleotides chemistry
Oligonucleotides pharmacology
Ribosome Inactivating Proteins, Type 1 chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 127
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 27823883
- Full Text :
- https://doi.org/10.1016/j.ejmech.2016.10.059