Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile
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...
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| Format: | Article |
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MDPI AG
2021-02-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/4/794 |
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| author | Adam Mieczkowski 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 Krzysztof Woźniak |
| author_facet | Adam Mieczkowski 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 Krzysztof Woźniak |
| author_sort | Adam Mieczkowski |
| collection | DOAJ |
| 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 <i>Caenorhabditis elegans</i> in the highest applied concentration of <b>6a,b</b> and <b>7a,b</b> (160 μM) and did not find any effect that would suggest disturbance to the life cycle of <i>Caenorhabditis elegans</i>. The lack of toxicity observed in <i>Caenorhabditis elegans</i> and enhanced, strengthened selectivity and activity toward the MCF7 cell line made <b>7a,b</b> good leading structures for further structure activity optimization and makes <b>7a,b</b> a reasonable starting point for the search of new, selective cytotoxic agents. |
| first_indexed | 2024-03-09T05:50:06Z |
| format | Article |
| id | doaj.art-529700a96a6149368266ec407e248c4b |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T05:50:06Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-529700a96a6149368266ec407e248c4b2023-12-03T12:17:46ZengMDPI AGMolecules1420-30492021-02-0126479410.3390/molecules26040794Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity ProfileAdam Mieczkowski0Elżbieta Speina1Damian Trzybiński2Maria Winiewska-Szajewska3Patrycja Wińska4Ewelina M. Borsuk5Małgorzata Podsiadła-Białoskórska6Tomasz Przygodzki7Krzysztof Drabikowski8Lidia Stanczyk9Igor Zhukov10Cezary Watala11Krzysztof Woźniak12Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, PolandInstitute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, PolandBiological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, PolandInstitute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, PolandFaculty of Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, PolandInstitute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, PolandInstitute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, PolandDepartment of Haemostatic Disorders, Chair of Biomedical Sciences, Faculty of Health Sciences, Medical University of Lodz, 6/8 Mazowiecka Street, 92-235 Lodz, PolandInstitute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, PolandDepartment of Haemostatic Disorders, Chair of Biomedical Sciences, Faculty of Health Sciences, Medical University of Lodz, 6/8 Mazowiecka Street, 92-235 Lodz, PolandInstitute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, PolandDepartment of Haemostatic Disorders, Chair of Biomedical Sciences, Faculty of Health Sciences, Medical University of Lodz, 6/8 Mazowiecka Street, 92-235 Lodz, PolandBiological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, PolandPhosphodiesterase 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 <i>Caenorhabditis elegans</i> in the highest applied concentration of <b>6a,b</b> and <b>7a,b</b> (160 μM) and did not find any effect that would suggest disturbance to the life cycle of <i>Caenorhabditis elegans</i>. The lack of toxicity observed in <i>Caenorhabditis elegans</i> and enhanced, strengthened selectivity and activity toward the MCF7 cell line made <b>7a,b</b> good leading structures for further structure activity optimization and makes <b>7a,b</b> a reasonable starting point for the search of new, selective cytotoxic agents.https://www.mdpi.com/1420-3049/26/4/794short peptidediketopiperazinetadalafilPDE5 inhibitorcytotoxicity |
| spellingShingle | Adam Mieczkowski 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 Krzysztof Woźniak Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile Molecules short peptide diketopiperazine tadalafil PDE5 inhibitor cytotoxicity |
| title | Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile |
| title_full | Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile |
| title_fullStr | Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile |
| title_full_unstemmed | Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile |
| title_short | Diketopiperazine-Based, Flexible Tadalafil Analogues: Synthesis, Crystal Structures and Biological Activity Profile |
| title_sort | diketopiperazine based flexible tadalafil analogues synthesis crystal structures and biological activity profile |
| topic | short peptide diketopiperazine tadalafil PDE5 inhibitor cytotoxicity |
| url | https://www.mdpi.com/1420-3049/26/4/794 |
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