Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Synthesis of peptides
Patent
1994-07-05
1997-11-04
Tsang, Cecilia J.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Synthesis of peptides
530333, 562442, C07K 104
Patent
active
056841310
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention is directed to a novel "handle" for solid phase peptide synthesis. The handles can be converted from a stable form to a labile form, allowing for cleavage of a peptide from the support after synthesis under mild conditions, and after deprotection of the protecting groups from the amino acid side chains. The handles are based on a substituted benzhydrylamine skeleton.
BACKGROUND OF THE INVENTION
As used in the art of peptide synthesis, the handle is defined as a bifunctional spacer that serves to link the peptide fragment or first amino acid to the polymer support. Many solid phase resins and handles are available in the art, as is described in Fields and Noble, 1990, Int. J. Pept. Protein Res. 35:161-214. To be useful, handles must be stable to the reaction conditions of peptide synthesis, but when the synthesis is complete, the handle needs to allow for cleavage of the peptide from the solid support.
A few handles that can be converted from a stable form of handle to a labile form have been designed and synthesized. Unfortunately, these handles have found no broad application in practice. For example, the 4-benzylthiophenyl- and 4-benzylsulfonyl-handle (D. L. Marshall, I. E. Liener: J. Org. Chem. 35, 867 (1970)) and sulfonamide-handle (G. W. Kenner, J. R. McDermott, R. C. Sheppard: Chem. Commun. 636, (1971)) have not found broad application. Further examples can be found in "The Peptides, Analysis, Synthesis, Biology," E. Gross, J. Meienhofer, Eds., Academic Press New York, vol. 2. p. 88 (1980), vol. 3. p. 209 (1981). Quite recently, the handle based on the 4-alkylthiobenzyl alcohol has been disclosed (EP 274,998 and EP 274,999; Chem. Abstr. 110, 135705 (1989)) and used in peptide synthesis. After reduction of the sulfoxide moiety, the 4-alkylthiobenzyl ester is cleaved to give a peptide with free carboxyl group.
The majority of aforementioned handles have, however, certain obvious limitations concerning the amino acid residues that can be affected by the conversion step. As a rule, oxidation steps cannot be used when the peptide contains sensitive amino acids such as tryptophan, cysteine, cystine, and methionine. Another problem is possible methylation during "activation" of handle and long cleavage times which can cause the damage of peptide.
Moreover, the handles presently available are not well adapted to both Boc and Fmoc synthetic procedures.
SUMMARY OF THE INVENTION
The instant invention is directed to substituted benzhydrylamine handles for peptide synthesis. The handles are prepared and used in acid labile form or in stable form. The stable form can be converted to an acid labile form for cleavage of the peptide from the resin.
The substituted benzhydrylamine handles are of the general formula (I): ##STR1## in which a=1 to 3, X.sup.1 is --GR.sup.1 or X.sup.1 is Z, the X.sup.1 groups are in the ortho or para positions of the first benzene ring, and R.sup.1 is a hydrocarbon group and ortho or para positions of the second benzene ring, and R.sup.2 is a hydrocarbon group; and by X.sup.1 unless X.sup.1 is Z, and R.sup.3 is a hydrocarbon group comprising a reactive functional group for coupling to a solid phase support, and in which if X.sup.1 is Z, Z is --GR.sup.3 in an ortho or para position; and group; and used herein, "hydrocarbon" can be a C.sub.1 to C.sub.10.
Further provided are methods for synthesis of the handles of the invention. In one embodiment, hydroxy or mercapto benzophenones are reacted with .omega.-haloesters of alkanecarboxylic acids in the presence of fluoride ions. The benzophenone carbonyl is subsequently converted to an amine by routine synthetic methods, e.g., reaction with hydroxylamine to yield an oxime, followed by reduction, e.g., with zinc, to yield benzhydrylamine, or by reductive amination, e.g., by reaction with ammonium formate. Alternatively the benzophenone can be reduced to the alcohol and amidated with an N.sup..alpha. -protected amino acid amide.
The present invention offers distinct advantages over earlier method
REFERENCES:
patent: 3963701 (1976-06-01), Grisar
Marshall et al., J. Org. Chem., 35:867 (1970).
Kenner et al., Chemical Commun. 636 (1971).
"The Peptide Analysis, Synthesis, Biology", E. Gross, J. Meienhofer Eds., Academic Press, New York, v.3, p.209, date not available.
Chemical Abstracts 110:135705 (1989).
Chemical Abstracts 115:183681S (1992).
Orlowski et al., J. Org. Chem. 41(23):3701-3705 (1976).
Funakoshi et al., Chem. Commun. 5:382-384 (1988).
Fields and Noble, Int. J. Pept. Res. 35:161-214 (1990).
Albercio et al., Int. J. Pept. Prot. Res. 30:206-216 (1987).
Carpino et al., Accounts of Chemical Research, 20:(11):401-407 (1987).
Patek, Tet Lett, 31, 5209, 1990.
Patek Tet Lett 32, 3891, 1991.
Lebl Michal
Patek Marcel
Lukton David
Tsang Cecilia J.
LandOfFree
Substituted benzhydrylamines as handles for solid phase peptide does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted benzhydrylamines as handles for solid phase peptide , we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted benzhydrylamines as handles for solid phase peptide will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1834019