Dear Richard,
We have prepared a great many head-to-tail cyclic peptides and
cyclic peptide libraries. Most of these have involved a side chain
attachment strategy which is also the subject of a recent US patent (A.
F. Spatola, K. Darlak, J. J. Wen, P. Romanovskis, "Cyclic peptide
mixtures via side chain or backbone attachment and solid phase
synthesis," December 28, 1999, United States Patent #6,008,058). A few
of our other references on this subject are also listed below.
Briefly, we use a procedure that we have extended to a large number
of trifunctional amino acids. After attaching the first amino acid (Asp,
Gln, Tyr, Lys, Orn, etc.) via its side chain, the peptide chain is
elongated, usually with Boc chemistry. In our hands, the allyl group has
not been as useful but others may advise you otherwise. We usually use
OFm esters (with proper precautions) or the para-nitrobenzyl group for
carboxyl protection. At this point, after removing only the end groups,
we cyclize on the resin, taking advantage of the "pseudo-dilution"
effect of the solid support. In most cases we then use HF to cleave the
peptide and deprotect remaining groups. With the ring sizes we use (5-8
residues) we have not had any significant problems with dimers. As I
said, details are in the references and as with any form of peptide
synthesis, the nature and amounts of messy reactions or by-products will
always be sequence dependent and must be expected to a certain extent.
But we have been able to test this concept using known activities and
have found several promising drug leads from our now growing variety of
structurally diverse mixtures.
I hope this helps and I wish you every success in your new research
endeavors. Best regards. Arno
P.S. The cyclizations are usually done in about an hour or two! Long
reaction times are in our experience due to blocked carboxyl groups and
thus misleadingly positive ninhydrin tests.
Arno F. Spatola, Yvon Crozet, Damiane deWit and Masashi Yanagisawa,
"Rediscovering BQ-123 (Endothelin
Antagonist): A Self-Deconvoluting Cyclic
Pentapeptide Library," J. Med. Chem., 39,
3842-3846 (1996).
James J. Wen and Arno F. Spatola, "A Systematic Approach for the
Solid
Phase Synthesis of Linear and Cyclic
Pseudopeptide Libraries Containing
Psi[CH2NH] Amide Bond Surrogates," J.
Peptide Res., 49, 3-14, (1997).
Peteris Romanovskis and Arno F. Spatola, "Head-to-Tail Cyclic Peptides
and Cyclic Peptide Libraries," In: The
Amide Linkage: Significance in
Chemistry, Biochemistry, and Materials
Science, Arthur Greenberg, Curt
Breneman, and Joel F. Liebman, Editors,
John Wiley, 2000, pp. 519-564.
Peteris Romanovskis and Arno F. Spatola, "Preparation of Head-to-Tail
Cyclic Peptides via Side Chain Attachment:
Implications for Library Synthesis,"
J. Peptide Research, 52, 356-374, 1998.
Yvon Crozet, James J. Wen, Rachel O. Loo, Philip C. Andrews, and Arno
F. Spatola, "Synthesis and
Characterization of Cyclic Pseudopeptide Libraries
Containing Thiomethylene and
Thiomethylene-sulfoxide Amide Bond
Surrogates," Molecular Diversity, 3,
261-267, 1998.
Peteris Romanovskis and Arno F. Spatola, "Expanding Diversity in
Cyclic
Peptide Libraries: Side Chain Attachment
Using Asp, Glu, Asn, Gln, Lys, Ser,
and Tyr for Initial Peptide Resin
Linkage," Peptides 1996, Proceedings of the
European Peptide Symposium, 1998, pp.
761-762.
-- Dr. Arno F. Spatola Department of Chemistry, University of Louisville Louisville, KY 40292-0001 USA email: spatola@louisville.edu Phone: 502-852-5979 Fax: 502-852-3899
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