Back to Search Start Over

Oligonucleotide transition state analogues of saporin L3.

Authors :
Mason JM
Yuan H
Evans GB
Tyler PC
Du Q
Schramm VL
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state analogues of Saporin L3 that mimic small oligonucleotide substrates in which the susceptible adenosine has been replaced by a 9-deazaadenyl hydroxypyrrolidinol derivative.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.)

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