Methods and compositions for controlled polypeptide synthesis
First Claim
1. A method of preparing a mixture containing an intermediate in combination with a solvent, wherein said intermediate is useful for making polypeptides, said method comprising reacting an NCA monomer with an initiator molecule in a suitable solvent to form the mixture containing the intermediate,wherein said initiator molecule comprises an amido-containing metallacycle, which contains a nucleophilic alkyl amido group stabilized by a rigid chelate and a non-nucleophilic proton-accepting group, and wherein the proton-accepting group is selected from the group consisting of a sulfonamidate, an amidate having an exocyclic carbonyl, a ureate, a carbamate and an aldimate.
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Abstract
Methods and compositions for the generation of polypeptides having varied material properties are disclosed herein. Methods include means for initiating the polymerization of aminoacid-N-carboxyanhydride (NCA) monomer by combining the monomer with an amido-containing metallacycle, for making self assembling amphiphilic block copolypeptides and related protocols for adding oligo(ethyleneglycol) functionalized aminoacid-N-carboxyanhydrides (NCAs) to polyaminoacid chains. Additional methods include means of adding an end group to the carboxy terminus of a polyaminoacid chain by reacting an alloc-protected amino acid amide with a transition metal-donor ligand complex to forming an amido-amidate metallacycle for use in further polymerization reactions. Novel compositions for use in peptide synthesis and design including five and six membered amido-containing metallacycles and block copolypeptides are also disclosed.
129 Citations
21 Claims
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1. A method of preparing a mixture containing an intermediate in combination with a solvent, wherein said intermediate is useful for making polypeptides, said method comprising reacting an NCA monomer with an initiator molecule in a suitable solvent to form the mixture containing the intermediate,
wherein said initiator molecule comprises an amido-containing metallacycle, which contains a nucleophilic alkyl amido group stabilized by a rigid chelate and a non-nucleophilic proton-accepting group, and wherein the proton-accepting group is selected from the group consisting of a sulfonamidate, an amidate having an exocyclic carbonyl, a ureate, a carbamate and an aldimate.
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8. A method for preparing a polypeptide comprising:
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initiating an alpha-amino N-carboxyanhydride (NCA) monomer polymerization by combining a NCA monomer with an initiator molecule, said initiator molecule comprising an amido-containing metallacyle, which contains a nucleophilic alkyl amido group stabilized by a rigid chelate and a non-nucleophilic proton-accepting group, wherein the proton accepting group is selected from the group consisting of a sulfonamidate, an amidate having an exocyclic carbonyl, a ureate, a carbamate and an aldimate;
polymerizing NCA monomers to form the polypeptide; and
isolating the polypeptide. - View Dependent Claims (9, 10, 11, 12, 13, 14)
wherein L is a Lewis base ligand;
n is an integer from 1 to 4;
M is a low valent transition metal;
R2, R3, R5, and R6 are each independently hydrogen or any organic substituent, provided said organic substituent does not bear a free amine, hydroxyl, carboxylic acid, sulfhydryl, isocyanate, imidazole, or a highly protic or nucleophilic functionality;
R4 and R6 are any organic substituent, provided said organic substituent does not bear a free amine, hydroxyl, carboxylic acid, sulfhydryl, isocyanate, imidazole, or a highly protic or nucleophilic functionality; and
X is oxygen or NH.
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12. The method of claim 11 wherein R2 and R6 are hydrogen and R3 and R5 are phenyl.
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13. The method of claim 11 wherein the Lewis base ligand of the initiator molecule is p-cymene.
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14. The method of claim 8 wherein the initiator molecule is of the following formula:
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wherein ts is tosyl and Ph is phenyl.
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15. A method for preparing a mixture which contains a polypeptide in combination with a solvent, said method comprising:
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A. initiating an alpha-amino N-carboxyanhydride (NCA) monomer polymerization by combining a NCA monomer with an initiator molecule in a suitable solvent, (1) wherein said initiator molecule comprises an amido-containing metallacyle, which contains a nucleophilic alkyl amido group stabilized by a rigid chelate and a non-nucleophilic proton-accepting group, and (2) wherein the proton accepting group is selected from the group consisting of a sulfonamidate, an amidate having an exocyclic carbonyl, a ureate, a carbamate and an aldimate; and
B. polymerizing NCA monomers to form a mixture comprising the polypeptide and the solvent. - View Dependent Claims (16, 17, 18, 19, 20, 21)
wherein L is a Lewis base ligand;
n is an integer from 1 to 4;
M is a low valent transition metal;
R2, R3, R5, and R6 are each independently hydrogen or any organic substituent, provided said organic substituent does not bear a free amine, hydroxyl, carboxylic acid, sulfhydryl, isocyanate, imidazole, or a highly protic or nucleophilic functionality;
R4 and R6 are any organic substituent, provided said organic substituent does not bear a free amine, hydroxyl, carboxylic acid, sulfhydryl, isocyanate, imidazole, or a highly protic or nucleophilic functionality; and
X is oxygen or NH.
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19. The method of claim 18 wherein R2 and R6 are hydrogen and R3 and R5 are phenyl.
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20. The method of claim 18 wherein the Lewis base ligand of the initiator molecule is p-cymene.
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21. The method of claim 15 wherein the initiator molecule is of the following formula:
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wherein ts is tosyl and Ph is phenyl.
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Specification