Thiosemicarbazates and uses thereof
View Patent ↗Thioesters, thiocarbamates, thiocarbazates, semithiocarbazates, peptides, aza-amino acid conjugates, and azapeptides; and a chemoselective and site-specific functionalization protocol of protected thiocarbazates and semithiocarbazates are described. The protocol features the use of Mitsunobu reaction to alkylate specifically the nitrogen atom close to the acylthiol moiety with alcohols to produce protected mono-substituted thiocarbazates that can be stored for months, activated under mild conditions at low temperature using halonium reagents and integrated orthogonally to make substituted semicarbazides that can be used, e.g., as synthons in synthesis of aza-amino acid conjugates, azapeptides and other peptidomimetics. Methods for preparing and using ureases, carbazides, semicarbazides, beta-peptides, azapeptides, and other peptidomimetics and azapeptide conjugates, and uses of ureases, carbazides, semicarbazides, beta-peptides, azapeptides in drug discovery, diagnosis, inhibition, prevention and treatment of diseases are also described.
1. A compound of the Formula (I):
wherein A is phthalimidyl, Y is a bond, X is NR 5 , D is an alkyl, and R 5 is a side chain radical of an amino acid.
2. The compound of claim 1 , wherein R 5 is the side chain radical of an amino acid selected from the group consisting of alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, threonine, cysteine, and glutamine.
3. The compound of claim 1 , which is of the formula
wherein R 5 is a side chain a side chain radical of an amino acid.
4. The compound of claim 3 , wherein R 5 is the side chain radical of an amino acid selected from the group consisting of alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, threonine, cysteine, and glutamine.
5. The compound of claim 3 , which is
6. A process for preparing a compound according to claim 1 comprising forming the compound of claim 1 by reacting a semi-protected hydrazine with a chlorothioformate to form an S-alkylthiocarbazate, and alkylating the resulting S-alkylthiocarbazate selectively via Mitsunobu reaction, a direct alkylation with NaH or with an alkyl halide.
7. A process for synthesizing an aza-peptide comprising activating a thioester with TCCA to form a reactive chloride, and coupling the reactive chloride with an amine, wherein the thioester is a compound according to claim 1 .
8. The process of claim 7 , wherein the aza-peptide is a compound of Formula (XVI):
wherein
is at the N-terminus and/or the C-terminus and/or at or adjacent to a cleavage and/or a hydrolysis site of the compound of Formula (XVI);
B is selected from the group consisting of hydrogen, —NH 2 , —CONH 2 , —COOR 19 , —COH, —COC 1 -C 4 alkyl, —COC 1 -C 4 haloalkyl, —OH, an amino acid, an aza amino acid, a 2 to 60-mer peptide, a 2 to 60-mer aza peptide, and a 2 to 60-mer azatide;
D is selected from the group consisting of —NH 2 , —NNH 2 , —NHCOCH 3 , —NHCH 3 , —N(CH 3 ) 2 , —CONH 2 , —COOH, —COH, —COC 1 -C 4 alkyl, —COC 1 -C 4 haloalkyl, an amino acid, an aza amino acid, a 2 to 60-mer peptide, a 2 to 60-mer aza peptide, and a 2 to 60-mer azatide;
R 19 is selected from the group consisting of C 1 -C 6 alkyl, methoxyl, ethoxyl, propoxyl, a C 1 -C 6 haloalkyl and a protecting group; and
R is selected from the group consisting of side chain radicals of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, threonine, cysteine, and glutamine.