# US 10,117,948 B2 · Selective arylation of dichalcogenides in biomolecules

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- Number: US 10,117,948 B2
- Document ID: US10117948B2
- Status: Granted
- Kind: B2
- Application number: 15/187,169
- Filed: 2016-06-20
- Published: 2016-12-22
- Granted: 2018-11-06
- Earliest claimed: 2015-06-19
- Assignees: Massachusetts Institute of Technology
- Applicants: Massachusetts Institute of Technology
- Inventors: Stephen L. Buchwald; Bradley L. Pentelute; Daniel T. Cohen; Chi Zhang
- Web page: https://patentgrep.com/patent/US10117948B2

## CPC

- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 38/14: Peptides containing saccharide radicals; Derivatives thereof {, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin}
- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- C07K 1/1075: {by covalent attachment of amino acids or peptide residues}
- C07K 1/1077: {by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids}
- C07K 1/13: Labelling of peptides
- C07K 9/008: {directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin}
- C07K 14/47: from mammals
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## 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.

## Claims

### Claim 1

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.

### Claim 2

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.

### Claim 3 (depends on 1)

A method of treating, killing or inhibiting the growth or proliferation of a bacterium, a fungus, a virus, or a parasite, comprising the step of:
contacting with the bacterium, fungus, virus, or parasite an effective amount of a compound of claim 1, thereby treating killing or inhibiting the growth or proliferation of the bacterium, fungus, virus, or parasite.

### Claim 4 (depends on 1)

A method of treating a disease in a subject in need thereof comprising the step of:
administering to the subject an effective amount of a compound of claim 1, thereby treating the disease.

### Claim 5 (depends on 1)

The compound of claim 1 comprising substructure I.

### Claim 6 (depends on 1)

The compound of claim 1, wherein
is a substituted phenyl radical selected from the group consisting of

### Claim 7 (depends on 1)

The compound of claim 1, wherein
is

### Claim 8 (depends on 1)

The compound of claim 1 comprising substructure II.

### Claim 9 (depends on 1)

The compound of claim 1, wherein is a substituted phenyl radical selected from the group consisting of

### Claim 10 (depends on 1)

The compound of claim 1, wherein
is