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Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile

Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland
Biological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland
Faculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland
Department of Haemostatic Disorders, Chair of Biomedical Sciences, Faculty of Health Sciences, Medical University of Lodz, 6/8 Mazowiecka Street, 92-235 Lodz, Poland
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editors: Joanna Bojarska, Wojciech M. Wolf, Milan Remko, Piotr Zielenkiewicz, Michele Saviano, Janusz Zabrocki and Krzysztof Kaczmarek
Molecules 2021, 26(4), 794;
Received: 8 January 2021 / Revised: 29 January 2021 / Accepted: 1 February 2021 / Published: 3 February 2021
(This article belongs to the Special Issue Advances in Research of Short Peptides)
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. View Full-Text
Keywords: short peptide; diketopiperazine; tadalafil; PDE5 inhibitor; cytotoxicity short peptide; diketopiperazine; tadalafil; PDE5 inhibitor; cytotoxicity
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MDPI and ACS Style

Mieczkowski, A.; Speina, E.; Trzybiński, D.; Winiewska-Szajewska, M.; Wińska, P.; Borsuk, E.M.; Podsiadła-Białoskórska, M.; Przygodzki, T.; Drabikowski, K.; Stanczyk, L.; Zhukov, I.; Watala, C.; Woźniak, K. Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile. Molecules 2021, 26, 794.

AMA Style

Mieczkowski A, Speina E, Trzybiński D, Winiewska-Szajewska M, Wińska P, Borsuk EM, Podsiadła-Białoskórska M, Przygodzki T, Drabikowski K, Stanczyk L, Zhukov I, Watala C, Woźniak K. Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile. Molecules. 2021; 26(4):794.

Chicago/Turabian Style

Mieczkowski, Adam, Elżbieta Speina, Damian Trzybiński, Maria Winiewska-Szajewska, Patrycja Wińska, Ewelina M. Borsuk, Małgorzata Podsiadła-Białoskórska, Tomasz Przygodzki, Krzysztof Drabikowski, Lidia Stanczyk, Igor Zhukov, Cezary Watala, and Krzysztof Woźniak. 2021. "Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile" Molecules 26, no. 4: 794.

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