Selective arylation of dichalcogenides in biomolecules
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.
1. A compound comprising
(a) substructure I:
wherein, independently for each occurrence,
A 1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A 5 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,
A 1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A 5 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.
2. A method
(a) according to Scheme 1:
wherein, independently for each occurrence,
A 1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A 5 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,
A 1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A 5 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,
A 1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A 2 , A 3 , and A 4 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;
A 5 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,
A 1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A 2 , A 3 , and A 4 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;
A 5 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,
A 1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A 5 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,
A 1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A 2 , A 3 , and A 4 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;
A 5 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,
A 1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A 2 , A 3 , and A 4 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;
A 5 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,
A 1 is H, an amine protecting group, a natural or unnatural amino acid, a peptide, an oligopeptide, a polypeptide, or a protein;
A 2 , A 3 , and A 4 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;
A 5 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.
3. 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.
4. 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.
5. The compound of claim 1 comprising substructure I.
6. The compound of claim 1 , wherein
is a substituted phenyl radical selected from the group consisting of
7. The compound of claim 1 , wherein
is
8. The compound of claim 1 comprising substructure II.
9. The compound of claim 1 , wherein is a substituted phenyl radical selected from the group consisting of
10. The compound of claim 1 , wherein
is