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    Calix[4]arene–pyrazole conjugates as potential cancer therapeutics

    Year: 2023

    Journal: Bioorganic Chemistry, Volume 139, 01/10/2023, page 106742

    Authors: Muravev, Anton A.; Voloshina, Alexandra D.; Sapunova, Anastasia S.; Gabdrakhmanova, Farida B.; Lenina, Oksana A.; Petrov, Konstantin A.; Shityakov, Sergey; Skorb, Ekaterina V.; Solovieva, Svetlana E.; Antipin, Igor S.

    Keywords: Langmuir monolayers; Calixarenes; Cervical carcinoma; DNA binding; DNA damage markers; Early apoptosis markers; Flow cytometry; Fluorescent microscopy; Pyrazoles

    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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