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Thermolytic Protecting Groups for Nucleosides in the Chemical Synthesis of Nucleic Acid Derivatives

Synthetic oligonucleotides can be used in a wide variety of settings, which include gene therapy treatments, diagnostic and DNA sequencing microarray technology, and basic research. The NIH announces an improvement in oligonucleotide syntheses for potential application on glass microarrays. This improvement entails the incorporation of thermolytic hydroxyl protecting groups derived from 2-aminopyridine and its analogues into nucleosides and their phosphoramidite derivatives. This novel class of 2-pyridyl-substituted hydroxyl protecting groups can be efficiently cleaved under mild thermolytic conditions without the use of harsh chemicals such as strong acids or bases. As an example, this technology uses thermal cleavage (brief heat treatment at temperatures up to 90°) of terminal 5'-hydroxyl protecting groups on a growing oligonucleotide chain without inducing the formation of reactive radicals, which is in contrast to the currently used photochemical deprotection methods. In addition, the mild neutral conditions employed in the thermolytic approach, will help prevent glass surfaces from being harmed by the harsh reagents that are still being used in conventional solid phase oligonucleotide synthesis. The thermal cleavage method also permits accurate monitoring of coupling efficiency after each chain elongation step by the use of fluorescent thermolytic groups for hydroxyl protection of nucleoside phosphoramidite monomers. Thus, these thermolabile groups could be useful in manufacturing synthetic oligonucleotides on solid supports or in solution. Also, thermolabile groups may be used to protect/deprotect drug functional groups under conditions that will not affect other protecting groups on the molecule.

Serge Beaucage
Marcin Chmielewski

Intellectual Property:
US Patent No. 7,612,197
US Application No. PCT/US2004/14185

Licensing Contact:
Bill Ronnenberg, JD-MIP, MS
FDA Technology Transfer Program
10903 New Hampshire Ave.
Building WO1, Rm 4214
Silver Spring, MD 20993
Email: FDAInventionlicensing@fda.hhs.gov
Phone: 240-402-4561

OTT Reference No: E-154-2003/0
Updated: August 9, 2015