Dipeptides of S-Substituted Dehydrocysteine as Artzyme Building Blocks: Synthesis, Complexing Abilities and Antiproliferative Properties

Abstract

Background: Dehydropeptides are analogs of peptides containing at least one conjugate double bond between α,β-carbon atoms. Its presence provides unique structural properties and reaction centre for chemical modification. In this study, the series of new class of dipeptides containing S-substituted dehydrocysteine with variety of heterocyclic moieties was prepared. The compounds were designed as the building blocks for the construction of artificial metalloenzymes (artzymes). Therefore, the complexing properties of representative compounds were also evaluated. Furthermore, the acknowledged biological activity of natural dehydropeptides was the reason to extend the study for antiproliferative action of against several cancer cell lines. Methods: The synthetic strategy involves glycyl and phenylalanyl-(Z)-β-bromodehydroalanine as a substrate in one pot addition/elimination reaction of thiols. After deprotection of N-terminal amino group the compounds with triazole ring were tested as complexones for copper(II) ions using potentiometric titration and spectroscopic techniques (UV-Vis, CD, EPR). Finally, the antiproliferative activity was evaluated by sulforhodamine B assay. Results and Conclusions: A simple and efficient procedure for preparation of dipeptides containing S-substituded dehydrocysteine was provided. The peptides containing triazole appeared to be strong complexones of copper(II) ions. Some of the peptides exhibited promising antiproliferative activities against number of cancer cell lines, including cell lines resistant to widely used anticancer agent.

Insight into the Structure of Victorin, the Host-Selective Toxin from the Oat PathogenCochliobolus victoriae. Studies of the Unique Dehydroamino Acid β-Chlorodehydroalanine

“…by comparison of the biological activity of semisynthetic isovictorins. It should be also noticed that the chlorovinyl function is a relatively reactive functional group, where the chlorine atom can be effectively changed by a nucleophile. ,, This opens a way to apply the β-chlorodehydroalanine residue in peptide design.…”

Synthesis of Hybrid Tripeptide Peptidomimetics Containing Dehydroamino Acid and Aminophosphonic Acid in the Chain and Evaluation of Their Activity toward Cathepsin C

“…These observations suggest, that dehydroamino acid residues are a useful tool allowing to change the peptide conformation, independently of the other constraints. The introduction of residues of dehydroamino acid into the bioactive peptide sequence has thus become a useful tool for studying the structure‐function relationship and providing new analogs of increased activity [16–18] …”

Imidazole-amino acids. Conformational switch under tautomer and pH change

“…The introduction of the azole structural motif in the peptide main chain in a post-translational modification (de Brevern and Rebehmed 2022 ) usually constrains its conformational flexibility (Soor et al 2018 ; Walker et al 2021 ). On the other hand, azole in the side chain can be used as building blocks for the construction of artificial metalloenzymes (Lenartowicz et al 2021 ). Azole rings can be also used as trans replacement agents (Kaczmarek et al 2021 ; Lenartowicz et al 2022 ).…”