US 10,117,948 B2Granted

Selective arylation of dichalcogenides in biomolecules

AssigneeMassachusetts Institute of Technology

InventorsStephen L. Buchwald, Bradley L. Pentelute, Daniel T. Cohen, Chi Zhang

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Abstract

Disclosed are chemical transformations for the conjugation of unprotected peptide biomolecules. The disclosed chemical transformations relate to methods of selective cysteine and selenocysteine functionalization of unprotected peptide and protein molecules. The processes feature several significant advantages over existing methods of peptide modification, including specificity towards selenocysteine over other nucleophiles (e.g., amines, hydroxyls), excellent functional group tolerance, and mild reaction conditions. Also disclosed are syntheses of arylated cysteine and arylated selenocysteine peptide compounds.

Claims10

Dependent claims

A compound comprising

(a) substructure I:
wherein, independently for each occurrence,
A1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A5 is OH, —O(carboxylate protecting group), a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
is a substituted phenyl radical selected from the group consisting of
x is 0, 1, 2, 3, 4, 5, or 6;
and
R is H or alkyl;
or
(b) substructure II:
wherein, independently for each occurrence,
A1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A5 is OH, —O(carboxylate protecting group), a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
is a substituted phenyl radical selected from the group consisting of
x is 0, 1, 2, 3, 4, 5, or 6;
and
R is H or alkyl.

14 more elements

A method

(a) according to Scheme 1:
wherein, independently for each occurrence,
A1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A5 is OH, —O(carboxylate protecting group), a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
is a substituted phenyl radical selected from the group consisting of
is a heteroaromatic moiety substituted with an electron withdrawing group;
x is 0, 1, 2, 3, 4, 5, or 6;
and
R is H or alkyl;
(b) according to Scheme 2:
wherein, independently for each occurrence,
A1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A5 is OH, —O(carboxylate protecting group), a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
is a substituted phenyl radical selected from the group consisting of
is a heteroaromatic moiety substituted with an electron withdrawing group;
x is 0, 1, 2, 3, 4, 5, or 6;
and
R is H or alkyl;
(c) according to Scheme 3:
wherein, independently for each occurrence,
A1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A2, A3, and A4 are selected from the group consisting of a natural amino acid, an unnatural amino acid, and a plurality of natural amino acids or unnatural amino acids;
A5 is OH, —O(carboxylate protecting group), a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
is a phenyl radical selected from the group consisting of
is a substituted phenyl diradical selected from the group consisting of
is a heteroaromatic moiety substituted with an electron withdrawing group;
x is 0, 1, 2, 3, 4, 5, or 6;
and
R is H or alkyl;
(d) according to Scheme 4:
wherein, independently for each occurrence,
A1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A2, A3, and A4 are selected from the group consisting of a natural amino acid, an unnatural amino acid, and a plurality of natural amino acids or unnatural amino acids;
A5 is OH, —O(carboxylate protecting group), a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
is a phenyl radical selected from the group consisting of
is a phenyl radical selected from the group consisting of
is a heteroaromatic moiety substituted with an electron withdrawing group;
x is 0, 1, 2, 3, 4, 5, or 6;
and
R is H or alkyl;
(e) according to Scheme 5:
wherein, independently for each occurrence,
A1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A5 is OH, —O(carboxylate protecting group), a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
is a substituted phenyl radical selected from the group consisting of
is a heteroaromatic moiety substituted with an electron withdrawing group;
x is 0, 1, 2, 3, 4, 5, or 6;
and
R is H or alkyl;
(f) according to Scheme 6:
wherein, independently for each occurrence,
A1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A2, A3, and A4 are selected from the group consisting of a natural amino acid, an unnatural amino acid, and a plurality of natural amino acids or unnatural amino acids;
A5 is OH, —O(carboxylate protecting group), a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
is a phenyl radical selected from the group consisting of
is a phenyl radical selected from the group consisting of
is a heteroaromatic moiety substituted with an electron withdrawing group;
x is 0, 1, 2, 3, 4, 5, or 6;
and
R is H or alkyl;
(g) according to Scheme 7:
wherein, independently for each occurrence,
A1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A2, A3, and A4 are selected from the group consisting of a natural amino acid, an unnatural amino acid, and a plurality of natural amino acids or unnatural amino acids;
A5 is OH, —O(carboxylate protecting group), a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
is a phenyl radical selected from the group consisting of
is a substituted phenyl diradical selected from the group consisting of
is a heteroaromatic moiety substituted with an electron withdrawing group;
x is 0, 1, 2, 3, 4, 5, or 6;
and
R is H or alkyl;
or
(h) according to Scheme 8:
wherein, independently for each occurrence,
A1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A2, A3, and A4 are selected from the group consisting of a natural amino acid, an unnatural amino acid, and a plurality of natural amino acids or unnatural amino acids;
A5 is OH, —O(carboxylate protecting group), a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
is a phenyl radical selected from the group consisting of
is a phenyl radical selected from the group consisting of
is a heteroaromatic moiety substituted with an electron withdrawing group;
x is 0, 1, 2, 3, 4, 5, or 6;
and
R is H or alkyl.

80 more elements

Dependencies are inferred from the claim text.

Facts

Application: 15/187,169Filed 20 Jun 2016 · us provisional application
Priority: 19 Jun 2015
Published: US 2016/0367693 A122 Dec 2016
Granted: 6 Nov 2018
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

A61K 47/6851
The modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site: the antibody targeting a determinant of a…
A61K 38/14
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: peptides containing saccharide radicals; Derivatives…
A61K 47/64
The modifying agent being a protein, peptide or polyamino acid: drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying…
C07K 1/1075
By covalent attachment of residues or functional groups: by covalent attachment of amino acids or peptide residues

Family

Application62/182,146Us provisional application · filed 19 Jun 2015
US 2016/0367693 A1Pre-grant publication · published 22 Dec 2016
US 10,117,948 B2This patent

From the US filing history. Foreign family members aren’t listed.

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