Novel antiproliferative agents bearing morpholinopyrimidine scaffold as PI3K inhibitors and apoptosis inducers; design, synthesis and molecular docking

Helwa, Amira Atef; El-Dydamony, Nehad M.; Radwan, Rasha Ali; Abdelraouf, Sahar M.; Abdelnaby, Rana M.

doi:10.1016/j.bioorg.2020.104051

Cited by 23 publications

(28 citation statements)

References 40 publications

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“…Compounds 1 26, 29 , 2 29, 30 , 3 26, 30 , and 5c 31 were prepared according to the reported procedure.…”

Section: Methodsmentioning

confidence: 99%

“…Then cells were washed in PBS, fixed in cold 70% ethanol for 30 min, washed twice in PBS, and centrifuged to remove supernatant, after that, cells were treated with 0.1 mg/ml ribonuclease, stained with 0.05 mg/ml PI. The results were analysed by flow cytometry using FACS calibre and cell cycle distribution were calculated and accomplished as reported 26 , 34 , 35 .…”

Section: Methodsmentioning

confidence: 99%

“…Cells were exposed to the tested compound for 48 h. After that, the cells were collected by trypsinisation and 0.5 × 10 6 cells and washed twice with phosphate-buffered saline (PBS) followed by staining with 5 µl Annexin-V-FITC and 5 µl PI in 1 × binding buffer for 15 min at room temperature in the dark. FACS Calibre flow cytometer (BD Biosciences, San Diego, CA) 26 , 36 , 37 was used for analyses.…”

Section: Methodsmentioning

confidence: 99%

“…In continuing our research work on developing pyrimidine derivatives acting on cell proliferation and apoptosis induction through PI3K/AKT axis inhibition, this work focussed on preparing new analogues derived from our previously reported lead compound ( VIII ) 26 keeping (4–(4-methoxyphenyl)-2-(methylthio)pyrimidine-5-carbonitrile) as the main core. Moreover, to study the effect of C-4 substitution on enzyme inhibition, ring variation and chain extension strategies were adopted via linking the pyrimidine core to substituted aryl moieties through different amino bridges one to four atoms in distance replacing the morpholine ring.…”

Section: Introductionmentioning

confidence: 99%

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Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562

El-Dydamony

Abdelnaby

Abdelhady

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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A novel series of 4-(4-Methoxyphenyl)-2-(methylthio)pyrimidine-5-carbonitrile was developed linked to an aromatic moiety via N -containing bridge and then evaluated for their cytotoxic activity against MCF-7 and K562 cell lines. Seven compounds exhibited the highest activity against both cell lines where compounds 4d and 7f were the most active against K562 cell line. Exploring their molecular mechanisms by enzyme inhibition assay on PI3Kδ/γ and AKT-1 showed that compound 7f was promising more than 4d with IC 50 = 6.99 ± 0.36, 4.01 ± 0.55, and 3.36 ± 0.17 uM, respectively. Also, flowcytometric analysis revealed that 7f caused cell cycle arrest at S-phase followed by caspase 3 dependent apoptosis induction. Mechanistically, compound 7f proved to modulate the expression of PI3K, p-PI3K, AKT, p-AKT, Cyclin D1, and NFΚβ. Furthermore, in-vivo toxicity study indicated good safety profile for 7f . These findings suggest that the trimethoxy derivative 7f has strong potential as a multi-acting inhibitor on PI3K/AKT axis targeting breast cancer and leukaemia.

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“…Compounds 1 26, 29 , 2 29, 30 , 3 26, 30 , and 5c 31 were prepared according to the reported procedure.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562

El-Dydamony

Abdelnaby

Abdelhady

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…Molecular modeling was done according to the reported procedures of [42,51,64] using DiscoveryStudio 4.1 software (Accelrys, Inc., San Diego, CA, USA). The X-ray 3D structures of VEGFR-2 (PDB ID: 3EWH) [48] and AKT-1 (PDB ID: 4EJN) [42,65] were obtained from the PDB site (http://www.rscb.org/pdb (accessed on 30 April 2022) and prepared for docking by cleaning the protein and fixing missing chains.…”

Section: Caspase-3 Evaluationmentioning

confidence: 99%

In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers

et al. 2022

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Protein kinases are seen as promising targets in controlling cell proliferation and survival in treating cancer where fused thiophene synthon was utilized in many kinase inhibitors approved by the FDA. Accordingly, this work focused on adopting fused thienopyrrole and pyrrolothienopyrimidine scaffolds in preparing new inhibitors, which were evaluated as antiproliferative agents in the HepG2 and PC-3 cell lines. The compounds 3b (IC50 = 3.105 and 2.15 μM) and 4c (IC50 = 3.023 and 3.12 μM) were the most promising candidates on both cells with good selective toxicity-sparing normal cells. A further mechanistic evaluation revealed promising kinase inhibitory activity, where 4c inhibited VEGFR-2 and AKT at IC50 = 0.075 and 4.60 μM, respectively, while 3b showed IC50 = 0.126 and 6.96 μM, respectively. Moreover, they resulted in S phase cell cycle arrest with subsequent caspase-3-induced apoptosis. Lastly, docking studies evaluated the binding patterns of these active derivatives and demonstrated a similar fitting pattern to the reference ligands inside the active sites of both VEGFR-2 and AKT (allosteric pocket) crystal structures. To conclude, these thiophene derivatives represent promising antiproliferative leads inhibiting both VEGFR-2 and AKT and inducing apoptosis in liver cell carcinoma.

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Anticancer Activities of Tetrasubstituted Imidazole‐Pyrimidine‐Sulfonamide Hybrids as Inhibitors of EGFR Mutants

et al. 2023

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A new series of tetrasubstituted imidazole derivatives carrying pyrimidine sulfonamide pharmacophores has been synthesized and evaluated for their anticancer activities. In‐vitro screening of these hybrids against a full 60‐cell‐line panel at a single dose of 10 μM showed significant growth inhibition of up to 95 %. The most active compound showed in‐vitro anticancer activities against (i) abnormal HER2 and (ii) two mutants for EGFR. Apoptotic gene expression revealed that lead compounds induced MCF‐7 cell line apoptosis together with considerable change in the Bax/Bcl‐2 expression ratio. One lead compound led to a significant cell‐cycle S‐phase arrest, while another blocked the cell cycle at G1/S‐phase causing the accumulation of cells. Docking analysis of these two hybrids adopted the orientation and binding interactions with a higher liability to enter the active side pocket of HER2, L858R, and T790 M, preferable to that of co‐crystallized ligands. Modelling simulation was consistent with the acquired biological evaluation.

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Novel antiproliferative agents bearing morpholinopyrimidine scaffold as PI3K inhibitors and apoptosis inducers; design, synthesis and molecular docking

Cited by 23 publications

References 40 publications

Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562

Pyrimidine-5-carbonitrile based potential anticancer agents as apoptosis inducers through PI3K/AKT axis inhibition in leukaemia K562

In Vitro Anticancer Activity Screening of Novel Fused Thiophene Derivatives as VEGFR-2/AKT Dual Inhibitors and Apoptosis Inducers

Anticancer Activities of Tetrasubstituted Imidazole‐Pyrimidine‐Sulfonamide Hybrids as Inhibitors of EGFR Mutants

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