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

Abstract

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.

Synthesis and neuroprotective activity of 3‐aryl‐3‐azetidinyl acetic acid methyl ester derivatives

“…The 19 F NMR spectrum revealed a chemical shift of CF 3 group at δ –62.6 ppm, which is in good agreement with the data reported in the literature. [ 58,59 ] Moreover, the 13 C NMR spectrum exhibited characteristic resonances of the 4‐trifluoromethylphenyl moiety, where the CF 3 group was observed as a quartet at δ 124.0 ppm ( 1 J C,F = 272.1 Hz), while the C‐4’ and C‐3’,5’ carbons appeared as quartets at δ 129.3 ppm ( 2 J C,F = 32.5 Hz) and δ 125.6 ppm ( 3 J C,F = 3.7 Hz), respectively. These assignments followed from the difference between the magnitudes of J C,F coupling constants.…”

Pyrazole-based lamellarin O analogues: synthesis, biological evaluation and structure–activity relationships

“…[29][30][31] Replacement of the central pyrrole to pyrazole is expected to change e.g., the energy of the highest occupied molecular orbital (HOMO) which is associated with increased metabolic stability. 32 In continuation of our previous works devoted to synthesis and investigation of pyrazole derivatives, [33][34][35][36][37][38][39][40][41] in this study we ought to synthesize and investigate various functionalized pyrazole derivatives of lamellarin O. The goal was based on the scaffold hopping of the pyrrole ring in natural lamellarin O to its pyrazole counterpart.…”

“…In continuation of our previous works devoted to synthesis and investigation of pyrazole derivatives, 33–41 in this study we ought to synthesize and investigate various functionalized pyrazole derivatives of lamellarin O. The goal was based on the scaffold hopping of the pyrrole ring in natural lamellarin O to its pyrazole counterpart.…”

Synthesis and Characterization of Novel Heterocyclic Chalcones from 1-Phenyl-1H-pyrazol-3-ol

“…Pyrazole derivatives are known to exhibit anti-inflammatory, analgesic, anticancer, antimicrobial, anti-infective and other activities [44][45][46][47]. In recent publications, we have reported the synthesis and antimitotic activity of 2,4-or 2,6-disubstituted-and 2,4,6-trisubstituted-2H-pyrazolo [4,3-c]pyridines [48], the antiproliferative activity of 2,4,6,7tetrasubstituted-2H-pyrazolo [4,3-c]pyridines [49], the photodynamic properties in the human skin melanoma cell line G361 of pyrazole-indole hybrids [50] and N-aryl-2,6-diphenyl-2H-pyrazolo [4,3-c]pyridin-7-amines [51] and the anthelmintic activity of benzopyrano [2,3c]pyrazol-4(2H)-ones [52].…”