Diversity-oriented synthesis of medicinally important 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives and higher analogs

Abstract

1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid (Tic) is a constrained analog of phenylalanine (Phe). The Tic unit has been identified as a core structural element present in several peptide-based drugs and forms an integral part of various biologically active compounds. This report covers the biological significance of the Tic core and provides a detailed account of various synthetic approaches available for the construction of Tic derivatives. Along with the traditional methods such as the Pictet-Spengler and Bischler-Nepieralski reactions, we cover various recent approaches such as enyne metathesis, [2 + 2 + 2] cycloaddition and the Diels-Alder reaction to generate Tic derivatives. In addition, syntheses of higher analogs of Tic are also discussed.

An Integrated Strategy for Assessing the Metabolic Stability and Biotransformation of Macrocyclic Peptides in Drug Discovery toward Oral Delivery

“…In addition, cleavage at the C-side of phenylalanine (F) at the P1 position was observed in G1 but not G2, suggesting that the primary cleavage took place at the C-side of arginine. Similar protection effects were also observed in G3 and G4 by incorporating a bulky unnatural amino acid at the carboxylic side of arginine, creating enhanced structural rigidity and proximal steric hindrance …”

“…Similar protection effects were also observed in G3 and G4 by incorporating a bulky unnatural amino acid at the carboxylic side of arginine, creating enhanced structural rigidity and proximal steric hindrance. 28 Based on previously reported enzyme specificity for pancreatic endopeptidases (i.e., trypsin, chymotrypsin, and elastase). 27,29−31 A majority of cleavage sites were successfully assigned to specific peptidases, excluding unnatural amino acids whose metabolizing peptidases were unclear.…”

An Integrated Strategy for Assessing the Metabolic Stability and Biotransformation of Macrocyclic Peptides in Drug Discovery toward Oral Delivery

“…In addition, cleavage at the C-side of phenylalanine (F) at the P1 position was observed in G1 but not G2, suggesting that the primary cleavage took place at the C-side of arginine. Similar protection effects were also observed in G3 and G4 by incorporating a bulky unnatural amino acid at the carboxylic side of arginine, creating enhanced structural rigidity and proximal steric hindrance …”

“…Similar protection effects were also observed in G3 and G4 by incorporating a bulky unnatural amino acid at the carboxylic side of arginine, creating enhanced structural rigidity and proximal steric hindrance. 28 Based on previously reported enzyme specificity for pancreatic endopeptidases (i.e., trypsin, chymotrypsin, and elastase). 27,29−31 A majority of cleavage sites were successfully assigned to specific peptidases, excluding unnatural amino acids whose metabolizing peptidases were unclear.…”

Synthesis of 1,2,3,4‐Tetrahydroisoquinoline‐3‐Carboxylic Acid‐Embedded Decapeptides: In Silico Studies and In Vitro Evaluation Against Breast Cancer

“…Developing the amphipathic peptides and conjugating with heterocyclic molecule can enhance its biological potency by improving the solubility in aqueous medium and can improve the stability of the compound [ 36 , 37 ]. Selectively incorporating conformationally constrained amino acid units into a peptide chain is a useful strategy to produce metabolically stable peptides with improved receptor selectivity [ 38 , 39 ]. The identification and selection of amino acids is based on the characteristics of specific functional groups and side chains of amino acids as they can modulate key cellular processes.…”

Succinct Syntheses of Methopholine, (±)‐Homolaudanosine, and (±)‐Dysoxyline via Metal‐free One‐Pot Double Alkylation on 1‐Methyl‐3,4‐dihydroisoquinolines

“…Through solvent screening processes, DCE and CH 3 CN turned out to be better than other solvents for the formation of double alkylating product 3a (entries [2][3][4][5][6]. As alkylation at the C1-methyl of iminium salt was known to be enabled by converting iminium salt to enamine with the help of bases, 31,32 addition of bases, such as Na 2 CO 3 , DIPEA, Et 3 N, DBU, and NMP, was performed in DCE and CH 3 CN (entries [7][8][9][10][11][12][13][14][15][16].…”

An Integrated Strategy for Assessing the Metabolic Stability and Biotransformation of Macrocyclic Peptides in Drug Discovery toward Oral Delivery

“…In addition, cleavage at the C-side of phenylalanine (F) at the P1 position was observed in G1 but not G2, suggesting that the primary cleavage took place at the C-side of arginine. Similar protection effects were also observed in G3 and G4 by incorporating a bulky unnatural amino acid at the carboxylic side of arginine, creating enhanced structural rigidity and proximal steric hindrance …”

“…Similar protection effects were also observed in G3 and G4 by incorporating a bulky unnatural amino acid at the carboxylic side of arginine, creating enhanced structural rigidity and proximal steric hindrance. 28 Based on previously reported enzyme specificity for pancreatic endopeptidases (i.e., trypsin, chymotrypsin, and elastase). 27,29−31 A majority of cleavage sites were successfully assigned to specific peptidases, excluding unnatural amino acids whose metabolizing peptidases were unclear.…”

Synthesis of 1,2,3,4‐Tetrahydroisoquinoline‐3‐Carboxylic Acid‐Embedded Decapeptides: In Silico Studies and In Vitro Evaluation Against Breast Cancer

“…Developing the amphipathic peptides and conjugating with heterocyclic molecule can enhance its biological potency by improving the solubility in aqueous medium and can improve the stability of the compound [ 36 , 37 ]. Selectively incorporating conformationally constrained amino acid units into a peptide chain is a useful strategy to produce metabolically stable peptides with improved receptor selectivity [ 38 , 39 ]. The identification and selection of amino acids is based on the characteristics of specific functional groups and side chains of amino acids as they can modulate key cellular processes.…”

Succinct Syntheses of Methopholine, (±)‐Homolaudanosine, and (±)‐Dysoxyline via Metal‐free One‐Pot Double Alkylation on 1‐Methyl‐3,4‐dihydroisoquinolines

“…Through solvent screening processes, DCE and CH 3 CN turned out to be better than other solvents for the formation of double alkylating product 3a (entries [2][3][4][5][6]. As alkylation at the C1-methyl of iminium salt was known to be enabled by converting iminium salt to enamine with the help of bases, 31,32 addition of bases, such as Na 2 CO 3 , DIPEA, Et 3 N, DBU, and NMP, was performed in DCE and CH 3 CN (entries [7][8][9][10][11][12][13][14][15][16].…”

An Integrated Strategy for Assessing the Metabolic Stability and Biotransformation of Macrocyclic Peptides in Drug Discovery toward Oral Delivery

“…In addition, cleavage at the C-side of phenylalanine (F) at the P1 position was observed in G1 but not G2, suggesting that the primary cleavage took place at the C-side of arginine. Similar protection effects were also observed in G3 and G4 by incorporating a bulky unnatural amino acid at the carboxylic side of arginine, creating enhanced structural rigidity and proximal steric hindrance …”

“…Similar protection effects were also observed in G3 and G4 by incorporating a bulky unnatural amino acid at the carboxylic side of arginine, creating enhanced structural rigidity and proximal steric hindrance. 28 Based on previously reported enzyme specificity for pancreatic endopeptidases (i.e., trypsin, chymotrypsin, and elastase). 27,29−31 A majority of cleavage sites were successfully assigned to specific peptidases, excluding unnatural amino acids whose metabolizing peptidases were unclear.…”

Synthesis of 1,2,3,4‐Tetrahydroisoquinoline‐3‐Carboxylic Acid‐Embedded Decapeptides: In Silico Studies and In Vitro Evaluation Against Breast Cancer

“…Developing the amphipathic peptides and conjugating with heterocyclic molecule can enhance its biological potency by improving the solubility in aqueous medium and can improve the stability of the compound [ 36 , 37 ]. Selectively incorporating conformationally constrained amino acid units into a peptide chain is a useful strategy to produce metabolically stable peptides with improved receptor selectivity [ 38 , 39 ]. The identification and selection of amino acids is based on the characteristics of specific functional groups and side chains of amino acids as they can modulate key cellular processes.…”

Succinct Syntheses of Methopholine, (±)‐Homolaudanosine, and (±)‐Dysoxyline via Metal‐free One‐Pot Double Alkylation on 1‐Methyl‐3,4‐dihydroisoquinolines

“…Through solvent screening processes, DCE and CH 3 CN turned out to be better than other solvents for the formation of double alkylating product 3a (entries [2][3][4][5][6]. As alkylation at the C1-methyl of iminium salt was known to be enabled by converting iminium salt to enamine with the help of bases, 31,32 addition of bases, such as Na 2 CO 3 , DIPEA, Et 3 N, DBU, and NMP, was performed in DCE and CH 3 CN (entries [7][8][9][10][11][12][13][14][15][16].…”