The solid phase combinatorial method is an excellent tool for the modulation of
protein-protein interactions through focused library generations. Nucleophilic aromatic
substitution reactions with an iodinated template on solid phase has opened a door for
easy and pure libraries of 13-22 membered medium and macrocyclic peptidomimetics.
These peptide mimics showed promising activities for tyrosine kinase receptors.
Iodine functionality can then be used to modify the products, on the resin, via
Sonogashira and Suzuki couplings and presumably through other organometallic
catalysis. The coupled products can have conformational biases that differ from the
iodinated macrocycles. These coupling reactions also provide a means to introduce
additional pharmacophores and to adjust the solubilities of the products.
The fluorinated template also gave libraries of cyclic peptidomimetics on solid phase
in good yields and purities. These libraries have improved water solubility over the
iodinated libraries. The 3-fluorinated template yielded better results than the 5-
fluorinated template. Some compounds showed biological activities in cell survival
assays providing strong support of our approach to mimic external ò-turn sequences in
target proteins.
Intrasite dimerization with 1,5-hexadiyne gave a homodimer as a byproduct. Solidphase
synthesis of bivalent turn mimics with fluorescent tags has been demonstrated.
The key feature of this synthetic route is that homo- and hetero-dimers can be formed
chemoselectively from unprotected monomeric precursors. The dimerization reaction is
very mild and versatile, as only potassium carbonate is required to affect the coupling.
Solution phase library synthesis of small molecule mimics is presented. Some
monomers of full sequence mimics have been prepared to afford dimer generations. Theses monomers were combined with linker handles to afford diverse length of dimers.
Final combination of monomers to make bivalent compounds is in progress.
| Identifer | oai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/4692 |
| Date | 25 April 2007 |
| Creators | Park, Chihyo |
| Contributors | Burgess, Kevin |
| Publisher | Texas A&M University |
| Source Sets | Texas A and M University |
| Language | en_US |
| Detected Language | English |
| Type | Book, Thesis, Electronic Dissertation, text |
| Format | 18218691 bytes, electronic, application/pdf, born digital |
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