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Oligonucleotide transition state analogues of saporin L3.

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state analogues of Saporin L3 that mimic small oligonucleotide substrates in which the susceptible adenosine has been replaced by a 9-deazaadenyl hydroxypyrrolidinol derivative.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 Ki values as low as 3.3 nM and indicating the structural requirements for inhibition.

SUBMITTER: Mason JM

PROVIDER: S-EPMC5296225 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Oligonucleotide transition state analogues of saporin L3.

Mason Jennifer M JM Yuan Hongling H Evans Gary B GB Tyler Peter C PC Du Quan Q Schramm Vern L VL

European journal of medicinal chemistry 20161027

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state analogues of Saporin L3 that mimic small oligonucleotide substrates in which the susceptible adenosine has been replaced by a 9-deazaadenyl ...[more]

PMID: 27823883

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