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Synthesis and Properties of Combinatorial Libraries of Phosphoramidates
journal contribution
posted on 1996-08-09, 00:00 authored by Reza Fathi, M. Jonathan Rudolph, Robert G. Gentles, Rina Patel, Eric W. MacMillan, Michael S. Reitman, David Pelham, Alan F. CookWe have assembled a set of combinatorial libraries of
phosphoramidates for pharmacological
evaluation. A range of functionalized and unfunctionalized diols,
representing a variety of diversity
elements, were converted into their corresponding dimethoxytrityl
H-phosphonate derivatives which
were coupled to each other to produce H-phosphonate dimers and trimers.
The H-phosphonate
diesters were converted into phosphoramidates by reaction with a wide
range of primary and
secondary amines. Very large libraries (theoretically, in excess
of one million compounds) possessing
five sites of diversity were generated for use in our drug discovery
program. Smaller libraries
with lower molecular weights were also prepared in which only two
monomeric units were coupled
together and converted into their phosphoramidate derivatives.
Methods for the attachment of
both radioactive and nonradioactive labels, including
32phosphorus, tritium, and fluorescein,
have
been developed. Representative single sequences were also prepared
and their chemical properties
studied.