Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines
A library of 2,4,6,7-tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines was prepared from easily accessible 1-phenyl-3-(2-phenylethynyl)-1<i>H</i>-pyrazole-4-carbaldehyde via an iodine-mediated electrophilic cyclization of intermediate 4-(azidomethyl)-1-ph...
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MDPI AG
2021-11-01
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| Online Access: | https://www.mdpi.com/1420-3049/26/21/6747 |
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| author | Beatričė Razmienė Eva Řezníčková Vaida Dambrauskienė Radek Ostruszka Martin Kubala Asta Žukauskaitė Vladimír Kryštof Algirdas Šačkus Eglė Arbačiauskienė |
| author_facet | Beatričė Razmienė Eva Řezníčková Vaida Dambrauskienė Radek Ostruszka Martin Kubala Asta Žukauskaitė Vladimír Kryštof Algirdas Šačkus Eglė Arbačiauskienė |
| author_sort | Beatričė Razmienė |
| collection | DOAJ |
| description | A library of 2,4,6,7-tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines was prepared from easily accessible 1-phenyl-3-(2-phenylethynyl)-1<i>H</i>-pyrazole-4-carbaldehyde via an iodine-mediated electrophilic cyclization of intermediate 4-(azidomethyl)-1-phenyl-3-(phenylethynyl)-1<i>H</i>-pyrazoles to 7-iodo-2,6-diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines followed by Suzuki cross-couplings with various boronic acids and alkylation reactions. The compounds were evaluated for their antiproliferative activity against K562, MV4-11, and MCF-7 cancer cell lines. The most potent compounds displayed low micromolar GI<sub>50</sub> values. 4-(2,6-Diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridin-7-yl)phenol proved to be the most active<b>,</b> induced poly(ADP-ribose) polymerase 1 (PARP-1) cleavage, activated the initiator enzyme of apoptotic cascade caspase 9, induced a fragmentation of microtubule-associated protein 1-light chain 3 (LC3), and reduced the expression levels of proliferating cell nuclear antigen (PCNA). The obtained results suggest a complex action of 4-(2,6-diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridin-7-yl)phenol that combines antiproliferative effects with the induction of cell death. Moreover, investigations of the fluorescence properties of the final compounds revealed 7-(4-methoxyphenyl)-2,6-diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridine as the most potent pH indicator that enables both fluorescence intensity-based and ratiometric pH sensing. |
| first_indexed | 2024-03-10T05:55:11Z |
| format | Article |
| id | doaj.art-c1e5ffbbb6c3420e803de16af82fd513 |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T05:55:11Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-c1e5ffbbb6c3420e803de16af82fd5132023-11-22T21:26:05ZengMDPI AGMolecules1420-30492021-11-012621674710.3390/molecules26216747Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridinesBeatričė Razmienė0Eva Řezníčková1Vaida Dambrauskienė2Radek Ostruszka3Martin Kubala4Asta Žukauskaitė5Vladimír Kryštof6Algirdas Šačkus7Eglė Arbačiauskienė8Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, LT-50254 Kaunas, LithuaniaDepartment of Experimental Biology, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech RepublicDepartment of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, LT-50254 Kaunas, LithuaniaDepartment of Experimental Physics, Faculty of Science, Palacký University, 17. Listopadu 12, CZ-77146 Olomouc, Czech RepublicDepartment of Experimental Physics, Faculty of Science, Palacký University, 17. Listopadu 12, CZ-77146 Olomouc, Czech RepublicDepartment of Chemical Biology, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech RepublicDepartment of Experimental Biology, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech RepublicDepartment of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, LT-50254 Kaunas, LithuaniaDepartment of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, LT-50254 Kaunas, LithuaniaA library of 2,4,6,7-tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines was prepared from easily accessible 1-phenyl-3-(2-phenylethynyl)-1<i>H</i>-pyrazole-4-carbaldehyde via an iodine-mediated electrophilic cyclization of intermediate 4-(azidomethyl)-1-phenyl-3-(phenylethynyl)-1<i>H</i>-pyrazoles to 7-iodo-2,6-diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines followed by Suzuki cross-couplings with various boronic acids and alkylation reactions. The compounds were evaluated for their antiproliferative activity against K562, MV4-11, and MCF-7 cancer cell lines. The most potent compounds displayed low micromolar GI<sub>50</sub> values. 4-(2,6-Diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridin-7-yl)phenol proved to be the most active<b>,</b> induced poly(ADP-ribose) polymerase 1 (PARP-1) cleavage, activated the initiator enzyme of apoptotic cascade caspase 9, induced a fragmentation of microtubule-associated protein 1-light chain 3 (LC3), and reduced the expression levels of proliferating cell nuclear antigen (PCNA). The obtained results suggest a complex action of 4-(2,6-diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridin-7-yl)phenol that combines antiproliferative effects with the induction of cell death. Moreover, investigations of the fluorescence properties of the final compounds revealed 7-(4-methoxyphenyl)-2,6-diphenyl-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridine as the most potent pH indicator that enables both fluorescence intensity-based and ratiometric pH sensing.https://www.mdpi.com/1420-3049/26/21/6747antiproliferationcell deathcross-couplingcycloiodinationpyrazolepyridine |
| spellingShingle | Beatričė Razmienė Eva Řezníčková Vaida Dambrauskienė Radek Ostruszka Martin Kubala Asta Žukauskaitė Vladimír Kryštof Algirdas Šačkus Eglė Arbačiauskienė Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines Molecules antiproliferation cell death cross-coupling cycloiodination pyrazole pyridine |
| title | Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines |
| title_full | Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines |
| title_fullStr | Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines |
| title_full_unstemmed | Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines |
| title_short | Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridines |
| title_sort | synthesis and antiproliferative activity of 2 4 6 7 tetrasubstituted 2 i h i pyrazolo 4 3 i c i pyridines |
| topic | antiproliferation cell death cross-coupling cycloiodination pyrazole pyridine |
| url | https://www.mdpi.com/1420-3049/26/21/6747 |
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