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

• Published in: Bioorganic chemistry Vol. 139; p. 106742
• Main 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.
• Format: Journal Article
• Language: English
• Published: SAN DIEGO Elsevier Inc 01.10.2023; Elsevier
• Subjects: Animals; Biochemistry & Molecular Biology; Calixarenes; Calixarenes - pharmacology; Cervical carcinoma; Chemistry; Chemistry, Organic; DNA binding; DNA damage markers; Early apoptosis markers; Flow cytometry; Fluorescent microscopy; HeLa Cells; Humans; Langmuir monolayers; Life Sciences & Biomedicine; Mice; Neoplasms - drug therapy; Physical Sciences; Porifera; Pyrazoles; Pyrazoles - pharmacology; Pyrazoles - therapeutic use; Science & Technology; PSD; Flow cytometry; Pyrazoles; Langmuir monolayers; MCF-7; EPR; DAPI; ctDNA; DNA binding; EMEM; TEA; SD; MFI; Fluorescent microscopy; DNA damage markers; Calixarenes; HC50; MDM2; Early apoptosis markers; PI; Cervical carcinoma; ATR; PATHWAYS; DOXORUBICIN; COMPLEXES; ARENE
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2023.106742

[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 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.