Synthesis and Antiproliferative Activity of 2,4,6,7-Tetrasubstituted-2H-pyrazolo[4,3-c]pyridines

Molecules

Asta Žukauskaitė¹  Eva Řezníčková²  Vladimír Kryštof²  Radek Ostruszka³  Martin Kubala³  Vaida Dambrauskienė⁴  Eglė Arbačiauskienė⁴  Algirdas Šačkus⁴  Beatričė Razmienė⁴ 

[1] Department of Chemical Biology, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic;Department of Experimental Biology, Palacký University, Šlechtitelů 27, CZ-78371 Olomouc, Czech Republic;Department of Experimental Physics, Faculty of Science, Palacký University, 17. Listopadu 12, CZ-77146 Olomouc, Czech Republic;Department of Organic Chemistry, Kaunas University of Technology, Radvilėnų pl. 19, LT-50254 Kaunas, Lithuania;

关键词: antiproliferation;    cell death;    cross-coupling;    cycloiodination;    pyrazole;    pyridine;   

DOI  :  10.3390/molecules26216747

来源: DOAJ

【 摘 要 】

A library of 2,4,6,7-tetrasubstituted-2H-pyrazolo[4,3-c]pyridines was prepared from easily accessible 1-phenyl-3-(2-phenylethynyl)-1H-pyrazole-4-carbaldehyde via an iodine-mediated electrophilic cyclization of intermediate 4-(azidomethyl)-1-phenyl-3-(phenylethynyl)-1H-pyrazoles to 7-iodo-2,6-diphenyl-2H-pyrazolo[4,3-c]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 GI₅₀ values. 4-(2,6-Diphenyl-2H-pyrazolo[4,3-c]pyridin-7-yl)phenol proved to be the most active, 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-2H-pyrazolo[4,3-c]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-2H-pyrazolo[4,3-c]pyridine as the most potent pH indicator that enables both fluorescence intensity-based and ratiometric pH sensing.

【 授权许可】

Unknown