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A facile synthesis of cysteine-based diketopiperazine from thiol-protected precursor.

ABSTRACT: l-Cysteine is one of the most promising biomass-based building blocks with great potential applications. Herein, we report a versatile synthetic route to produce cysteine-based 2,5-diketopiperazine (DKP) with good yield from the thiol-ene click reaction of l-cysteine and commercially available acrylates, followed by dimerization of the amino acid intermediates. The achieved DKP diastereomers were successfully separated and fully characterized by spectroscopic methods. Moreover, the chiroptical property of DKP in the presence of various metal ions was investigated by circular dichroism spectroscopy. The potential application of the optically active cysteine-based DKP as a chiral probe for detection of silver ion in water has been demonstrated.

SUBMITTER: Zhang D

PROVIDER: S-EPMC6030340 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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A facile synthesis of cysteine-based diketopiperazine from thiol-protected precursor.

Zhang Di D Wang Wayne W

Royal Society open science 20180620 6

l-Cysteine is one of the most promising biomass-based building blocks with great potential applications. Herein, we report a versatile synthetic route to produce cysteine-based 2,5-diketopiperazine (DKP) with good yield from the thiol-ene click reaction of l-cysteine and commercially available acrylates, followed by dimerization of the amino acid intermediates. The achieved DKP diastereomers were successfully separated and fully characterized by spectroscopic methods. Moreover, the chiroptical p ...[more]

PMID: 30110492

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Project description:Phosphodiesterase 5 (PDE5) is one of the most extensively studied phosphodiesterases that is highly specific for cyclic-GMP hydrolysis. PDE5 became a target for drug development based on its efficacy for treatment of erectile dysfunction. In the present study, we synthesized four novel analogues of the phosphodiesterase type 5 (PDE5) inhibitor-tadalafil, which differs in (i) ligand flexibility (rigid structure of tadalafil vs. conformational flexibility of newly synthesized compounds), (ii) stereochemistry associated with applied amino acid building blocks, and (iii) substitution with bromine atom in the piperonyl moiety. For both the intermediate and final compounds as well as for the parent molecule, we have established the crystal structures and performed a detailed analysis of their structural features. The initial screening of the cytotoxic effect on 16 different human cancer and non-cancer derived cell lines revealed that in most cases, the parent compound exhibited a stronger cytotoxic effect than new derivatives, except for two cell lines: HEK 293T (derived from a normal embryonic kidney, that expresses a mutant version of SV40 large T antigen) and MCF7 (breast adenocarcinoma). Two independent studies on the inhibition of PDE5 activity, based on both pure enzyme assay and modulation of the release of nitric oxide from platelets under the influence of tadalafil and its analogues revealed that, unlike a reference compound that showed strong PDE5 inhibitory activity, the newly obtained compounds did not have a noticeable effect on PDE5 activity in the range of concentrations tested. Finally, we performed an investigation of the toxicological effect of synthesized compounds on Caenorhabditis elegans in the highest applied concentration of 6a,b and 7a,b (160 μM) and did not find any effect that would suggest disturbance to the life cycle of Caenorhabditis elegans. The lack of toxicity observed in Caenorhabditis elegans and enhanced, strengthened selectivity and activity toward the MCF7 cell line made 7a,b good leading structures for further structure activity optimization and makes 7a,b a reasonable starting point for the search of new, selective cytotoxic agents.

Dataset Information

A facile synthesis of cysteine-based diketopiperazine from thiol-protected precursor.

Publications

A facile synthesis of cysteine-based diketopiperazine from thiol-protected precursor.

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