1. Diversity-oriented synthesis of medicinally important 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) derivatives and higher analogs
Sambasivarao Kotha, Deepak Deodhar, Priti Khedkar Org Biomol Chem. 2014 Dec 7;12(45):9054-91. doi: 10.1039/c4ob01446d.
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.
2. Discovery and development of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives as Bcl-2/Mcl-1 inhibitors
Renshuai Liu, Lulu Liu, Xinying Yang, Hao Fang Bioorg Chem. 2019 Jul;88:102938. doi: 10.1016/j.bioorg.2019.102938. Epub 2019 Apr 20.
Bcl-2 family proteins play a vital role for cancer cell in escaping apoptosis, and small-molecule anti-apoptotic Bcl-2 protein inhibitors have been developed as new anticancer therapies. In current study, a series of substituted 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid derivatives were developed based on the lead compound 1 (Ki = 5.2 µM against Bcl-2 protein). The fluorescence polarization assays suggested that active compounds possessed potent binding affinities to both Bcl-2 and Mcl-1 protein, but had minor or no binding affinities to Bcl-XL protein. MTT assays showed that these compounds had certain anti-proliferative activities against cancer cells. Furthermore, it was found that active compound 11t could induce cell apoptosis and caspase-3 activation in a dose-dependent manner in Jurkat cells.
3. Applications and modifications of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in peptides and peptidomimetics design and discovery
Yingjie Zhang, Hao Fang, Wenfang Xu Curr Protein Pept Sci. 2010 Dec;11(8):752-8. doi: 10.2174/138920310794557691.
Tic, short for 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, is a kind of unnatural α-amino acids. Due to its distinct geometrical conformation and biological activity, the structure of Tic, regarded as the surrogate of proline and the rigid analogue of phenylalanine or tyrosine, has been introduced into many compounds, which target diverse enzymes or receptors. The most successful example is that substituting the Tic residue for the proline residue of enalapril led to an approved drug quinapril. In this review, we will summarize the applications and modifications of Tic in peptides and peptidomimetics design and discovery, and hope to spark medicinal researchers' inspiration in the field of protein and peptide drug design and optimization.
