Discover TIQ and TIC as Proline Analogs

In this blog, we present 1-carboxy-derivatives of 1,2,3,4-tetrahydroisoquinoline (TIQ) as novel proline analogs. They can act as helix breakers and may be used to fine-tune the secondary and tertiary structure of synthetic peptides. TIQs also have been successfully used in the design of specific inhibitors for the protease Cas-2, where TIQs modulate the affinity to the active center, in the synthesis of promising matrix metalloproteinase (MMP) inhibitors and for gonadotropin-releasing hormone (GnRH) receptor antagonists.

Overview of available Fmoc-protected TIQs as novel proline analogs: The 1-carboxy 1,2,3,4-tetrahydroisoquinolines are provided enantomerically pure; the methyl-substituted ones as racemates. 

These Fmoc-protected building blocks can be directly used in Fmoc solid-phase peptide synthesis. Especially, the differently methyl-substituted derivatives are perfect for screening, e.g., to fine-tune the structure-activity relationship of your inhibitory molecule or ligand. 

Schematic depiction of the steric consequences using the (S) and (R) varieties of our TIQs: The axial or equatorial orientation of the carboxy group affects the structure of the peptide chain, analog to proline.

Furthermore, we are also offering Fmoc- and Boc-protected as well as unprotected 3-carboxy 1,2,3,4-tetrahydroisoquinolines (TIC derivatives) and -hydroxyisoquinolines with similar properties. For structure details, please scroll-down to the related products at the bottom of this blog!

References: 

Exploiting differences in caspase-2 and -3 S2 subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors; M. C. Maillard, F. A. Brookfield, S. M. Courtney, F. M. Eustache, M. J. Gemkow, R. K. Handel, L. C. Johnson, P. D. Johnson, M. A. Kerry, F. Krieger, M. Meniconi, I.Munoz-Sanjuán, J. J. Palfrey, H. Park, S. Schaertl, M. G. Taylor, D. Weddell, C. Dominguez; Bioorg. Med. Chem. 2011; 19(19): 5833-5851. https://doi.org/10.1016/j.bmc.2011.08.020

Caspase-2 Inhibitor Blocks Tau Truncation and Restores Excitatory Neurotransmission in Neurons Modeling FTDP-17 Tauopathy; G. Singh, P. Liu, K. R. Yao, J. M. Strasser, C. Hlynialuk, K. Leinonen-Wright, P. J. Teravskis, J. M. Choquette, J. Ikramuddin, M. Bresinsky, K. M. Nelson, D. Liao, K. H. Ashe, M. A. Walters, S. Pockes; ACS Chem. Neurosci. 2022; 13(10): 1549-1557. https://doi.org/10.1021/acschemneuro.2c00100

Molecular and Conformational Determinants of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) for Activation of the PAC1 Receptor; S. Bourgault, D. Vaudry, I. Ségalas-Milazzo, L. Guilhaudis, A. Couvineau, M. Laburthe, H. Vaudry, A. Fournier; J. Med. Chem. 2009; 52(10): 3308-3316. https://doi.org/10.1021/jm900291j

Development and Pharmacological Characterization of Conformationally Constrained Urotensin II-Related Peptide Agonists; D. Chatenet, B. Folch, D. Feytens, M. Létourneau, D. Tourwé, N. Coucet, A. Fournier; J. Med. Chem. 2013; 56(23): 9612-9622. https://doi.org/10.1021/jm401153j

Discovery of a Parenteral Small Molecule Coagulation Factor XIa Inhibitor Clinical Candidate (BMS-962212); D. J. P. Pinot, M. J. Orwat, L. M. Smith, M. L. Quan, P. Y. S. Lam, K. A. Rossi, A. Apedo, J. M. Bozarth, Y. Wu, J. J. Zheng, B. Xin, N. Toussaint, P. Stetsko, O. Gudmundsson, B. Maxwell, E. J. Crain, P. C. Wong, Z. Lou, T. W. Harper, S. A. Chacko, J. E. Myers, S. Sheriff, H. Zhang, X. Hou, A. Mathur, D. A. Seiffert, R. R. Wexler, J. M. Luettgen, W. R. Ewing; J. Med. Chem. 2017; 60(23): 9703-9723. https://doi.org/10.1021/acs.jmedchem.7b01171