Novel Bis-Thiazole Derivatives: Synthesis and Potential Cytotoxic Activity Through Apoptosis With Molecular Docking Approaches

Abstract

A series of bis-thiazoles 5a–g were synthesized from bis-thiosemicarbazone 3 with hydrazonoyl chlorides 4a–g. Reaction of 3 with two equivalents of α-halocarbonyl compounds 6–8, 10, and 12a–d afforded the corresponding bis-thiazolidines 9, 11, and 13a–d, respectively. Condensation of bis-thiazolidin-4-one 9 with different aromatic aldehydes furnished bis-thiazolidin-4-ones 14a–d. Compounds 5a–g, 9, and 13a,c,d were screened in vitro for their cytotoxic activities in a panel of cancer cell lines. Compounds 5a–c, 5f–g, and 9 exhibited remarkable cytotoxic activities, especially compound 5c with potent IC50 value 0.6 nM (against cervical cancer, Hela cell line) and compound 5f with high IC50 value 6 nM (against ovarian cancer, KF-28 cell line). Compound 5f–induced appreciated apoptotic cell death was measured as 82.76% associated with cell cycle arrest at the G1 phase. The apoptotic pathways activated in KF-28 cells treated with 5a, 5b, and 5f were further investigated. The upregulation of some pro-apoptotic genes, bax and puma, and the downregulation of some anti-apoptotic genes including the Bcl-2 gene were observed, indicating activation of the mitochondrial-dependent apoptosis. Together with the molecular docking studies of compounds 5a and 5b, our data revealed potential Pim-1 kinase inhibition through their high binding affinities indicated by inhibition of phosphorylated C-myc as a downstream target for Pim-1 kinase. Our study introduces a set of bis-thiazoles with potent anti-cancer activities, in vitro.

WITHDRAWN: Synthesis, characterization and computational studies of 2-amino-4-substituted thiazoles, their divalent nickel and cobalt complexes and molecular docking studies of their ligands as potent μ-opioid receptor agonists

“…The thiazole ring is a structural component of natural compounds such as Vitamin B 1 , penicillin and carboxylase (Maupin-Furlow, 2018). In addition, drugs containing sulfathiazole, phthalylsulfatiazole and their derivatives (such as famotidine, thiabendazole, epothilone and meloxicam) are frequently used in human medicine (Dawood et al, 2021;Samuel et al, 2021;Yurttaş et al, 2021). An interesting use of thiazoles has been reported by Stangeland and Sammakia (2004) in the halogen dance reaction for the total synthesis of WS75624 B.…”

Design, synthesis, molecular modelling and antitumor evaluation of S -glucosylated rhodanines through topo II inhibition and DNA intercalation

“…The IC50 values for compound 6 were then used to treat HepG2 cells for 48 h. Afterwards, the standard operating procedure called for an RT-PCR reaction to be performed. The Ct values were then used to determine the relative expression of each gene in each sample, normalised to the β-actin as house-keeping gene 90–92 .…”

Design, Synthesis, Computational Investigations, and Antitumor Evaluation ofN-Rhodanine Glycosides Derivatives as Potent DNA Intercalation and Topo II Inhibition against Cancer Cells

“…The next step involved collecting medium supernatants and cells and rinsing them with ice-cold PBS. The next step was suspending the cells in 100 μL of annexin binding buffer solution 25 mM CaCl 2 , 1.4 M NaCl, and 0.1 M Hepes/NaOH, pH 7.4, and incubation with Annexin V-FITC solution (1:100) and propidium iodide (PI) at a concentration equaling 10 μg/mL in the dark for 30 min. − …”