Calix[4]arene–pyrazole conjugates as potential cancer therapeutics
[Display omitted] •Calixarene pyrazoles show low hemolysis, low mutagenicity, and low in vivo toxicity.•NH-pyrazolated phenol ether and calixarenes stereoisomers inhibit M-HeLa cell growth.•Internal pathway of caspase-9 activation in M-HeLa cell lines treated by pyrazoles.•Upregulated DNA damage mar...
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Veröffentlicht in: | Bioorganic chemistry 2023-10, Vol.139, p.106742-106742, Article 106742 |
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Sprache: | eng |
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•Calixarene pyrazoles show low hemolysis, low mutagenicity, and low in vivo toxicity.•NH-pyrazolated phenol ether and calixarenes stereoisomers inhibit M-HeLa cell growth.•Internal pathway of caspase-9 activation in M-HeLa cell lines treated by pyrazoles.•Upregulated DNA damage markers and M-HeLa cell-cycle halt after pyrazole treatment.•Monolayers of calixarene pyrazoles expand at air–water interface in presence of DNA.
Tumor selectivity is yet a challenge in chemotherapy-based cancer treatment. A series of calixarenes derivatized at the lower rim with 3-phenyl-1H-pyrazole units with variable upper-rim substituent and conformations of macrocyclic core, alkyl chain length between heterocycle and core, as well as phenolic monomer (5-(4-tert-butylphenyloxy)methoxy-3-phenyl-1H-pyrazole) have been synthesized and characterized in a range of therapeutically relevant cellular models (M-HeLa, MCF7, A-549, PC3, Chang liver, and Wi38) from different target organs/systems. Specific cytotoxicity for M-HeLa cells has been observed in tert-butylcalix[4]arene pyrazoles in 1,3-alternate (compound 7b) and partial cone (compound 7c) conformations with low mutagenicity and haemotoxicity and in vivo toxicity in mice. Compounds 7b,c have induced mitochondrial pathway of apoptosis of M-HeLa cells through caspase-9 activation preceded by the cell cycle arrest at G0/G1 phase. A concomitant overexpression of DNA damage markers in pyrazole-treated M-HeLa cells suggests that calixarene pyrazoles target DNA, which was supported by the presence of interactions between calixarenes and ctDNA at the air–water interface. |
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ISSN: | 0045-2068 1090-2120 |
DOI: | 10.1016/j.bioorg.2023.106742 |