Oligonucleotide transition state analogues of saporin L3

Jennifer M. Mason, Hongling Yuan, Gary B. Evans, Peter C. Tyler, Quan Du, Vern L. Schramm

Research output: Contribution to journalArticle

1 Citation (Scopus)

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state analogues of Saporin L3 that mimic small oligonucleotide substrates in which the susceptible adenosine has been replaced by a 9-deazaadenyl hydroxypyrrolidinol derivative.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

Original languageEnglish (US)
Pages (from-to)793-809
Number of pages17
JournalEuropean Journal of Medicinal Chemistry
Volume127
DOIs
StatePublished - Feb 15 2017

Fingerprint

Ribosome Inactivating Proteins
Oligonucleotides
Toxicity
Poisons
Refractory materials
Adenosine
Blood Vessels
Clinical Trials
Derivatives
Substrates
saporin
Neoplasms
Therapeutics

Keywords

  • Aza-sugar
  • Oligonucleotide
  • Ribosome inactivating protein
  • Saporin
  • Transition state inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Oligonucleotide transition state analogues of saporin L3. / Mason, Jennifer M.; Yuan, Hongling; Evans, Gary B.; Tyler, Peter C.; Du, Quan; Schramm, Vern L.

In: European Journal of Medicinal Chemistry, Vol. 127, 15.02.2017, p. 793-809.

Research output: Contribution to journalArticle

Mason, Jennifer M. ; Yuan, Hongling ; Evans, Gary B. ; Tyler, Peter C. ; Du, Quan ; Schramm, Vern L. / Oligonucleotide transition state analogues of saporin L3. In: European Journal of Medicinal Chemistry. 2017 ; Vol. 127. pp. 793-809.
@article{51ea85bfd82a4145a3e93e65945ac09b,
title = "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.",
keywords = "Aza-sugar, Oligonucleotide, Ribosome inactivating protein, Saporin, Transition state inhibitor",
author = "Mason, {Jennifer M.} and Hongling Yuan and Evans, {Gary B.} and Tyler, {Peter C.} and Quan Du and Schramm, {Vern L.}",
year = "2017",
month = "2",
day = "15",
doi = "10.1016/j.ejmech.2016.10.059",
language = "English (US)",
volume = "127",
pages = "793--809",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

}

TY - JOUR

T1 - Oligonucleotide transition state analogues of saporin L3

AU - Mason, Jennifer M.

AU - Yuan, Hongling

AU - Evans, Gary B.

AU - Tyler, Peter C.

AU - Du, Quan

AU - Schramm, Vern L.

PY - 2017/2/15

Y1 - 2017/2/15

N2 - 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.

AB - 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.

KW - Aza-sugar

KW - Oligonucleotide

KW - Ribosome inactivating protein

KW - Saporin

KW - Transition state inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85006137974&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85006137974&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2016.10.059

DO - 10.1016/j.ejmech.2016.10.059

M3 - Article

C2 - 27823883

AN - SCOPUS:85006137974

VL - 127

SP - 793

EP - 809

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

ER -