New thiazol-hydrazono-coumarin hybrids targeting human cervical cancer cells: Synthesis, CDK2 inhibition, QSAR and molecular docking studies

El-Karim, Somaia S. Abd; Syam, Yasmin M.; Kerdawy, Ahmed M. El; Abdelghany, Tamer M.

doi:10.1016/j.bioorg.2019.01.026

Cited by 71 publications

(33 citation statements)

References 72 publications

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“…As a member of the protein kinase family, CDK2 participates in the regulation of the eukaryotic cell division cycle [ 34 ]. Apart from the fact that a previous study uncovered that CDK2-related signaling pathways conferred complicated roles in several forms of cancers [ 35 ], a few studies have investigated the tumor-promoting role of CDK2 in CC [ 36 – 38 ]. In another research, bioinformatics analysis authenticated that the CDK2-related signaling pathway was involved in CC [ 39 ].…”

Section: Introductionmentioning

confidence: 99%

circ_0084927 promotes cervical carcinogenesis by sponging miR-1179 that suppresses CDK2, a cell cycle-related gene

Zhu

Song

et al. 2020

Cancer Cell Int

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Background: Cervical cancer (CC) is a malignant tumor found in the lowermost part of the womb. Evolving studies on CC have reported that circRNA plays a crucial role in CC progression. In this study, we investigated the main function of a novel circRNA, circ_0084927, and its regulatory network in CC development. Methods: qRT-PCR was applied to evaluate the expression of circ_0084927, miR-1179, and CDK2 mRNA in CC tissues and cells. Dual-luciferase reporting experiments and RNA immunoprecipitation (RIP) assay were conducted to validate the target relationship of miR-1179 with circ_0084927 and CDK2 mRNA. CCK-8 and BrdU assays were also used to evaluate CC cell proliferation. The adhesion and apoptosis phenotypes of CC cells were measured using cell-matrix adhesion and caspase 3 activation assay. Flow cytometry was also employed to detect the CC cell cycle. Results: Our results indicated that circ_0084927 was up-regulated in CC tissues and cells. Findings also revealed that circ_0084927 silence inhibited CC cell proliferation and adhesion while facilitating apoptosis and triggering cell cycle arrest. However, miR-1179 down-regulation appeared in CC tissues. Apart from observing that circ_0084927 abolished miR-1179's inhibitory effects on cell proliferation and adhesion, it was found that CDK2 was up-regulated in CC tissues and was instrumental in cancer promotion. Also observed was that miR-1179 directly targeted CDK2, thereby inhibiting CDK2's promotion on the malignant phenotypes of CC cells. Lastly, results indicated that circ_0084927 revoked the inhibitory effect of miR-1179 on CDK2 by sponging miR-1179. Conclusion: circ_0084927 promoted cervical carcinogenesis by sequestering miR-1179, which directly targeted CDK2. Our results also provided novel candidate targets for CC treatment in that it revealed the circ_0084927/miR-1179/CDK2 regulatory network that strengthened CC aggressiveness.

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Section: Introductionmentioning

confidence: 99%

circ_0084927 promotes cervical carcinogenesis by sponging miR-1179 that suppresses CDK2, a cell cycle-related gene

Zhu

Song

et al. 2020

Cancer Cell Int

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“…A previous study uncovered that CDK2-related signaling pathways conferred complicated roles in several cancers [35]. A few studies have been conducted to study the tumor promoting role of CDK2 in CC [36][37][38]. Besides, a previous bioinformatics analysis authenticated that CDK2-related signaling pathways was involved in CC [39].…”

Section: Introductionmentioning

confidence: 99%

Circ_0084927 promotes cervical carcinogenesis by sponging miR-1179 that suppresses CDK2, a cell cycle-related gene

Zhu

Song

et al. 2020

Preprint

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Background: Cervical cancer (CC) is a highly malignant tumor. Evolving researches on CC have unveiled a concept that circRNA exerts important roles in CC progression. In this study, we mainly explored the role of a novel circRNA, circ_0084927, and its regulatory network in the development of CC. Methods: qRT-PCR was applied to evaluate the expression of circ_0084927, miR-1179 and CDK2 mRNA in CC tissues and cells. Dual-luciferase reporting experiments and RNA immunoprecipitation (RIP) assay were conducted to validate the target relationship of miR-1179 with circ_0084927 and CDK2 mRNA. CCK-8 and BrdU assay was used to evaluate CC cell proliferation. The adhesion and apoptosis phenotypes of CC cells were measured by cell-matrix adhesion and caspase 3 activation assay. Flow cytometry was employed to detect CC cell cycle. Results: Our results indicated that circ_0084927 was up-regulated in CC tissues and cells, and circ_0084927 silence inhibited CC cell proliferation and adhesion, while facilitating apoptosis as well as triggering cell cycle arrest. On the other hand, miR-1179 down-regulation appeared in CC tissues. Additionally, circ_0084927 abolished miR-1179’s inhibitory effects on cell proliferation and adhesion. Our study showed that CDK2 was up-regulated in CC tissues and played a cancer-promoting role. Furthermore, miR-1179 directly targeted CDK2, thereby inhibiting CDK2’s promotion on the malignant phenotypes of CC cells. circ_0084927 revoked the inhibitory effect of miR-1179 on CDK2 by sponging miR-1179. Conclusion: Circ_0084927 promoted cervical carcinogenesis by sequestering miR-1179 that directly targeted CDK2. Our results shed light on the circ_0084927/miR-1179/CDK2 regulatory network that strengthened CC aggressiveness, providing novel candidate targets for CC treatment.

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“…These complexes are responsible for the progression of the cell cycle through its different phases [5,6]. This key role of CDKs in cell cycle progression makes them potential targets for cancer treatment and makes their inhibitors promising for targeted chemotherapy [7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole–Indole Conjugates as Anticancer CDK Inhibitors

Al-Warhi,

El Kerdawy,

Aljaeed

et al. 2020

Molecules

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On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole–indole conjugates (6a–i and 9a–f) and carbocycle–indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC50: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC50: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (6a–h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC50s equal 1.82 and 1.26 µM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.

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New thiazol-hydrazono-coumarin hybrids targeting human cervical cancer cells: Synthesis, CDK2 inhibition, QSAR and molecular docking studies

Cited by 71 publications

References 72 publications

circ_0084927 promotes cervical carcinogenesis by sponging miR-1179 that suppresses CDK2, a cell cycle-related gene

circ_0084927 promotes cervical carcinogenesis by sponging miR-1179 that suppresses CDK2, a cell cycle-related gene

Circ_0084927 promotes cervical carcinogenesis by sponging miR-1179 that suppresses CDK2, a cell cycle-related gene

Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole–Indole Conjugates as Anticancer CDK Inhibitors

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