Design, synthesis, biological evaluation of 3,5-diaryl-4,5-dihydro-1H-pyrazole carbaldehydes as non-purine xanthine oxidase inhibitors: Tracing the anticancer mechanism via xanthine oxidase inhibition

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dc.contributor.authorJoshi, Gaurav
dc.contributor.authorSharma, Manisha
dc.contributor.authorKalra, Sourav
dc.contributor.authorGavande, Navnath S.
dc.contributor.authorSingh, Sandeep
dc.contributor.authorKumar, Raj
dc.date.accessioned2024-01-21T10:38:15Z
dc.date.accessioned2024-08-13T12:05:09Z
dc.date.available2024-01-21T10:38:15Z
dc.date.available2024-08-13T12:05:09Z
dc.date.issued2021-01-07T00:00:00
dc.description.abstractXanthine oxidase (XO) has been primarily targeted for the development of anti-hyperuriciemic /anti-gout agents as it catalyzes the conversion of xanthine and hypoxanthine into uric acid. XO overexpression in various cancer is very well correlated due to reactive oxygen species (ROS) production and metabolic activation of carcinogenic substances during the catalysis. Herein, we report the design and synthesis of a series of 3,5-diaryl-4,5-dihydro-1H-pyrazole carbaldehyde derivatives (2a-2x) as xanthine oxidase inhibitors (XOIs). A docking model was developed for the prediction of XO inhibitory activity of our novel compounds. Furthermore, our compounds anticancer activity results in low XO expression and XO-harboring cancer cells both in 2D and 3D-culture models are presented and discussed. Among the array of synthesized compounds, 2b and 2m emerged as potent XO inhibitors having IC50 values of 9.32 � 0.45 �M and 10.03 � 0.43 �M, respectively. Both compounds induced apoptosis, halted the cell cycle progression at the G1 phase, elevated ROS levels, altered mitochondrial membrane potential, and inhibited antioxidant enzymes. The levels of miRNA and expression of redox sensors in cells were also altered due to increase oxidative stress induced by our compounds. Compounds 2b and 2m hold a great promise for further development of XOIs for the treatment of XO-harboring tumors. � 2021 Elsevier Inc.en_US
dc.identifier.doi10.1016/j.bioorg.2020.104620
dc.identifier.issn452068
dc.identifier.urihttp://10.2.3.109/handle/32116/3506
dc.identifier.urlhttps://linkinghub.elsevier.com/retrieve/pii/S0045206820319180
dc.language.isoen_USen_US
dc.publisherAcademic Press Inc.en_US
dc.subject2-pyrazolinesen_US
dc.subject2D-QSAR docking modelen_US
dc.subjectMitochondrial membrane permeabilityen_US
dc.subjectReactive oxygen speciesen_US
dc.subjectRedox sensoren_US
dc.subjectXanthine oxidaseen_US
dc.titleDesign, synthesis, biological evaluation of 3,5-diaryl-4,5-dihydro-1H-pyrazole carbaldehydes as non-purine xanthine oxidase inhibitors: Tracing the anticancer mechanism via xanthine oxidase inhibitionen_US
dc.title.journalBioorganic Chemistryen_US
dc.typeArticleen_US
dc.type.accesstypeClosed Accessen_US

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