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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| Autores principales: | , , , , , , , , |
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| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
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| Materias: | |
| Acceso en línea: | https://doaj.org/article/c1e5ffbbb6c3420e803de16af82fd513 |
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| Sumario: | 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. |
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