Design, synthesis and in vitro anti-proliferative evaluation of new pyridine-2,3-dihydrothiazole/thiazolidin-4-one hybrids as dual CDK2/GSK3β kinase inhibitors.

Autor: Kassem AF; Chemistry of Natural and Microbial Products Department, National Research Centre Dokki 12622 Cairo Egypt., Sediek AA; Chemical Industries Institute, National Research Centre Dokki 12622 Cairo Egypt., Omran MM; Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University Cairo Egypt., Foda DS; Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre Dokki 12622 Cairo Egypt aisha_pharmacy@yahoo.com., Al-Ashmawy AAK; Therapeutic Chemistry Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre Dokki 12622 Cairo Egypt aisha_pharmacy@yahoo.com.
Jazyk: angličtina
Zdroj: RSC advances [RSC Adv] 2024 Oct 07; Vol. 14 (43), pp. 31607-31623. Date of Electronic Publication: 2024 Oct 07 (Print Publication: 2024).
DOI: 10.1039/d4ra06146b
Abstrakt: Herein, the molecular hybridization drug discovery approach was used in the design and synthesis of twelve novel pyridine-2,3-dihydrothiazole hybrids (2a,b-5a,b and 13a,b-14a,b) and fourteen pyridine-thiazolidin-4-one hybrids (6a,b-12a,b) as anti-proliferative analogues targeting CDK2 and GSK3β kinase inhibition. Almost all of the newly synthesized hybrids, including their precursors (1a,b), were evaluated for their anti-proliferative activity against three human cancer cell lines-MCF-7, HepG2 and HEp-2-as well as normal Vero cell lines. Both compounds 1a (pyridine-thiourea precursor) and 8a (pyridine-5-acetyl-thiazolidin-4-one hybrid) exhibited excellent anti-proliferative activity against HEp-2 (IC 50 = 7.5 μg mL -1 , 5.9 μg mL -1 , respectively). Additionally, 13a (pyridine-5-( p -tolyldiazenyl-2,3-dihydrothiazole)) hybrid demonstrated excellent anti-proliferative activity against HepG2 (IC 50 = 9.5 μg mL -1 ), with an acceptable safety profile against Vero (<45% inhibition at 100 μg mL -1 ) in the cases of 8a and 13a alone. The three promising anti-proliferative hybrids (1a, 8a, 13a) were selected for the assessment of their in vitro inhibitory kinase activity against CDK2/GSK3β using roscovitine (IC 50 = 0.88 μg mL -1 ) and CHIR-99021 (IC 50 = 0.07 μg mL -1 ) as references, respectively. Compound 13a was the most potent dual CDK2/GSK3β inhibitor (IC 50 = 0.396 μg mL -1 , 0.118 μg mL -1 , respectively) followed by 8a (IC 50 = 0.675 μg mL -1 , 0.134 μg mL -1 , respectively), and the weakest was 1a. To elucidate the mechanism of the most potent anti-proliferative 13a hybrid, further cell cycle analysis was performed revealing that it caused G1 cell cycle arrest and induced apoptosis. Moreover, it resulted in an increase in Bax and caspase-3 with a decrease in Bcl-2 levels in HepG2 cells compared with untreated cells. Finally, in silico drug likeness/ADME prediction for the three potent compounds as well as a molecular docking simulation study were conducted in order to explore the binding affinity and interactions in the binding site of each enzyme, which inspired their usage as anti-proliferative leads for further modification.
Competing Interests: There is no conflict to declare.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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