Unusual Amino Acids in Medicinal Chemistry

Abstract

Unusual amino acids are fundamental building blocks of modern medicinal chemistry. The combination of readily functionalized amine and carboxyl groups attached to a chiral central core along with one or two potentially diverse side chains provides a unique three-dimensional structure with a high degree of functionality. This makes them invaluable as starting materials for syntheses of complex molecules, highly diverse elements for SAR campaigns, integral components of peptidomimetic drugs, and potential drugs on their own. This Perspective highlights the diversity of unnatural amino acid structures found in hit-to-lead and lead optimization campaigns and clinical stage and approved drugs, reflecting their increasingly important role in medicinal chemistry.

Chiral Heterocycle-Based Receptors for Enantioselective Recognition

“…Tetracationic cyclophane, (R)-14.4PF 6 was obtained by the reaction of (R)-12 and 13.2PF 6 and similarly D 2 symmetric tetracationic cyclophane, (R,R)-16.4PF 6 was synthesized using the treatment of (R)-12 and (R)-15.2PF 6 . These tetracationic cyclophane receptors were found to be effective for the chiral recognition in the case of several chiral amino acids, such as L-and D-enantiomers of phenylalanine (Phe), tyrosine (Tyr), and tryptophane (Trp) as free forms, or methyl esters, or N-acetyls in H 2 O and organic solvents, as determined by using UV-Vis titration.…”

“…Table 9. Binding constant (K a ), the Gibbs free energy changes (∆G 0 ), enantioselectivities K R /K S or ∆∆G 0 for including the R/S guest with the chiral host macrocycles in DMSO-d 6 Yilmaz Turgut et al [73] synthesized four C 2 -symmetric chiral pyridine containing 18-crown-6 macrocycles, each containing pairs of the following substituents: ethyl (107), isopropyl (108), phenyl (109), and benzyl (110). The synthetic strategy adopted was as follows: firstly, as a chiral source, D-Val, D-Phgly and D-Phe were reduced to the corresponding amino alcohols, D-valinol, 104b, D-Phenyl glycinol 104c and D-phenylalaninol, 104d.…”

“…The dibromide salts, 158a-c.2Br − and 159a-c.2Br − were obtained by the direct quaternization of 157a-c with 2,6-di(bromomethyl)-4-chlorophenol or 1,3-bis(bromomethyl)benzene or 2,6-bis(bromomethyl)pyridine while the hexafluorophosphate salts 158a-c.2PF 6 − and 159a-c.2PF 6 − were prepared by the treatment with a saturated aqueous solution of NH 4 PF 6 . The chiral discrimination of chiral molecular tweezers for amino acids or their derivatives (Tables 15 and 16) were evaluated by the UV-vis titration method.…”

“…[6]helicenes-based supramolecular chirogenic system (214) for chiral recognition of enantiopure trans-1,2-cyclohexanediamine ( Figure 20). The host, 214 was obtained using the reaction of dioxa [6]helicenes and (1S)-camphanic chloride and the Complexation of host pophoric acid, 205A mode, with guest, 206 (2-AP) gave the highest ∆ ε value at 498.65 cm −1 M −1 . Similarly, the 205B mode resulted in highest ∆ ε value of 641.13 cm −1 M −1 for 211 (2-AMB) (Table 19).…”

“…Various biological phenomena such as enzyme-substrate, antibody-antigen and drug-biomolecule interactions are a manifestation of the importance of enantiospecific supramolecular processes in living organisms [4]. The importance of chirality in the fields of medicine [5,6], asymmetric synthesis, [7,8] catalysis [9], flavor [10], fragrances [11], biochemistry [12] and material science chemistry [13] has already been well established. While the area of asymmetric synthesis has witnessed a tremendous growth, the practicality of preparing homochiral compounds still remains a challenge.Thus, the stimulus for interest in the separation of racemic mixtures exploiting host-guest chemistry has gained popularity over the years.…”