Biochemical, Structural Analysis, and Docking Studies of Spiropyrazoline Derivatives
In this study, we evaluated the antiproliferative potential, DNA damage, crystal structures, and docking calculation of two spiropyrazoline derivatives. The main focus of the research was to evaluate the antiproliferative potential of synthesized compounds towards eight cancer cell lines. Compound &...
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| Format: | Article |
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MDPI AG
2022-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/11/6061 |
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| author | Angelika A. Adamus-Grabicka Mateusz Daśko Pawel Hikisz Joachim Kusz Magdalena Malecka Elzbieta Budzisz |
| author_facet | Angelika A. Adamus-Grabicka Mateusz Daśko Pawel Hikisz Joachim Kusz Magdalena Malecka Elzbieta Budzisz |
| author_sort | Angelika A. Adamus-Grabicka |
| collection | DOAJ |
| description | In this study, we evaluated the antiproliferative potential, DNA damage, crystal structures, and docking calculation of two spiropyrazoline derivatives. The main focus of the research was to evaluate the antiproliferative potential of synthesized compounds towards eight cancer cell lines. Compound <b>I</b> demonstrated promising antiproliferative properties, especially toward the HL60 cell line, for which IC<sub>50</sub> was equal to 9.4 µM/L. The analysis of DNA damage by the comet assay showed that compound <b>II</b> caused DNA damage to tumor lineage cells to a greater extent than compound <b>I</b>. The level of damage to tumor cells of the HEC-1-A lineage was 23%. The determination of apoptotic and necrotic cell fractions by fluorescence microscopy indicated that cells treated with spiropyrazoline-based analogues were entering the early phase of programmed cell death. Compounds <b>I</b> and <b>II</b> depolarized the mitochondrial membranes of cancer cells. Furthermore, we performed simple docking calculations, which indicated that the obtained compounds are able to bind to the PARP1 active site, at least theoretically (the free energy of binding values for compound <b>I</b> and <b>II</b> were −9.7 and 8.7 kcal mol<sup>−1</sup>, respectively). In silico studies of the influence of the studied compounds on PARP1 were confirmed in vitro with the use of eight cancer cell lines. The degradation of the PARP1 enzyme was observed, with compound <b>I</b> characterized by a higher protein degradation activity. |
| first_indexed | 2024-03-10T01:16:31Z |
| format | Article |
| id | doaj.art-d616b3377c834243a3c754b08c61379b |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:16:31Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-d616b3377c834243a3c754b08c61379b2023-11-23T14:08:56ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-05-012311606110.3390/ijms23116061Biochemical, Structural Analysis, and Docking Studies of Spiropyrazoline DerivativesAngelika A. Adamus-Grabicka0Mateusz Daśko1Pawel Hikisz2Joachim Kusz3Magdalena Malecka4Elzbieta Budzisz5Department of Bioinorganic Chemistry, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, PolandDepartment of Inorganic Chemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza 11/12, 80-233 Gdansk, PolandDepartment of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, PolandInstitute of Physics, University of Silesia, 75 Pulku Piechoty 1, 41-500 Chorzow, PolandDepartment of Physical Chemistry, Faculty of Chemistry, University of Lodz, Pomorska 163/165, 90-236 Lodz, PolandDepartment of the Chemistry of Cosmetic Raw Materials, Faculty of Pharmacy, Medical University of Lodz, Muszynskiego 1, 90-151 Lodz, PolandIn this study, we evaluated the antiproliferative potential, DNA damage, crystal structures, and docking calculation of two spiropyrazoline derivatives. The main focus of the research was to evaluate the antiproliferative potential of synthesized compounds towards eight cancer cell lines. Compound <b>I</b> demonstrated promising antiproliferative properties, especially toward the HL60 cell line, for which IC<sub>50</sub> was equal to 9.4 µM/L. The analysis of DNA damage by the comet assay showed that compound <b>II</b> caused DNA damage to tumor lineage cells to a greater extent than compound <b>I</b>. The level of damage to tumor cells of the HEC-1-A lineage was 23%. The determination of apoptotic and necrotic cell fractions by fluorescence microscopy indicated that cells treated with spiropyrazoline-based analogues were entering the early phase of programmed cell death. Compounds <b>I</b> and <b>II</b> depolarized the mitochondrial membranes of cancer cells. Furthermore, we performed simple docking calculations, which indicated that the obtained compounds are able to bind to the PARP1 active site, at least theoretically (the free energy of binding values for compound <b>I</b> and <b>II</b> were −9.7 and 8.7 kcal mol<sup>−1</sup>, respectively). In silico studies of the influence of the studied compounds on PARP1 were confirmed in vitro with the use of eight cancer cell lines. The degradation of the PARP1 enzyme was observed, with compound <b>I</b> characterized by a higher protein degradation activity.https://www.mdpi.com/1422-0067/23/11/6061flavonoid derivativesanticancer propertiesspiropyrazolinePARP1DNA interaction |
| spellingShingle | Angelika A. Adamus-Grabicka Mateusz Daśko Pawel Hikisz Joachim Kusz Magdalena Malecka Elzbieta Budzisz Biochemical, Structural Analysis, and Docking Studies of Spiropyrazoline Derivatives International Journal of Molecular Sciences flavonoid derivatives anticancer properties spiropyrazoline PARP1 DNA interaction |
| title | Biochemical, Structural Analysis, and Docking Studies of Spiropyrazoline Derivatives |
| title_full | Biochemical, Structural Analysis, and Docking Studies of Spiropyrazoline Derivatives |
| title_fullStr | Biochemical, Structural Analysis, and Docking Studies of Spiropyrazoline Derivatives |
| title_full_unstemmed | Biochemical, Structural Analysis, and Docking Studies of Spiropyrazoline Derivatives |
| title_short | Biochemical, Structural Analysis, and Docking Studies of Spiropyrazoline Derivatives |
| title_sort | biochemical structural analysis and docking studies of spiropyrazoline derivatives |
| topic | flavonoid derivatives anticancer properties spiropyrazoline PARP1 DNA interaction |
| url | https://www.mdpi.com/1422-0067/23/11/6061 |
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