Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents

Aliwaini, Saeb; Thaher, Bassam A. Abu; Almasri, Ihab M.; Shurrab, Nabil Kh.; El‐Kurdi, Said; Schollmeyer, Dieter; Qeshta, Basem; Ghunaim, Mariam Jamal; Csuk, René; Laufer, Stefan; Kaiser, Lars; Deigner, Hans‐Peter

doi:10.3390/molecules26134065

Cited by 17 publications

(21 citation statements)

References 43 publications

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“…Docking result suggested that thioxanthones TX3 ‐ 6 were active against cancer cells that express EGFR protein. The cancer cells that express EGFR protein were in breast, [25] cervical, [26] lung, [27] and colorectal cancer [28] . Therefore, the synthesized thioxanthones TX3 ‐ 6 were evaluated through the MTT assay against breast (T47D), cervical (HeLa), colorectal (WiDr), and lung (A549) cancer cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…[20,21] In many cases, PDGFR protein is often overexpressed in the lung, [18] breast, [22] glioma, [23] and ovarian [24] cancer cell lines. While EGFR protein is expressed in breast, [25] cervical, [26] lung, [27] and colorectal [28] cancer cells. In our previous work on the molecular docking study of thioxanthone derivatives, it was revealed that the important factors influencing their binding energy were the presence of hydroxyl and halogen (i. e., chloro (Cl) and bromo (Br)) substituents.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Docking Approach For Design and Synthesis of Thioxanthone Derivatives as Anticancer Agents

et al. 2022

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Thioxanthone derivatives were docked, synthesized, and tested for their anticancer activity. The molecular docking results showed that 1-hydroxythioxanthone, 2-chloro-1-hydroxythioxanthone, and 4-chloro-1-hydroxythioxanthone gave lower binding energy than erlotinib demonstrating that those thioxanthones have stronger interaction in the active site of EGFR protein. The addition of one hydroxyl and chloro groups on 1-hydroxythioxanthone greatly enhanced its inhibition in EGFR protein. All thioxanthone derivatives had hydrogen bonding interaction with MET769 residue. The in vitro anti-cancer assay against all cancer cells (T47D, HeLa, WiDr, A549) revealed that 2-chloro-1-hydroxythioxanthone and 4-chloro-1hydroxythioxanthone gave lower IC 50 than 1-hydroxythioxanthone due to the addition of one chloro substituent. Meanwhile, 1,3-dihydroxythioxanthone exhibited the strongest anticancer activity, as well as the highest selectivity index (3.22-19.55) among the other thioxanthones. Based on these findings, 1,3-dihydroxythioxanthone is a potential anticancer drug candidate for further development in the future.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Docking Approach For Design and Synthesis of Thioxanthone Derivatives as Anticancer Agents

et al. 2022

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“…The synthesized compounds were evaluated for their cytotoxic activity by a photometric rhodamine B assay (SRB) on different human cancer cell lines, malignant melanoma (A375), colon (HT29), breast (MCF-7), human ovarian carcinoma (A2780) and pharynx carcinoma (FaDu); for comparison, non-malignant mouse embryonic fibroblasts (NIH 3T3) and human embryonic kidney cells (HEK293) were included; doxorubicin (DX) was used as a positive control [ 31 , 32 ]. The results are summarized in Table 1 .The EC 50 values in μM from SRB assays were determined after 72 h of treatment, and the values are averaged from three independent experiments performed each in triplicate, confidence interval, CI = 95%; mean ± standard mean error).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and In Silico Docking of New Pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine-based Cytotoxic Agents

Horchani

Heise

Hoenke

et al. 2021

IJMS

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To explore a new set of anticancer agents, a novel series of pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine derivativeshave been designed and synthesized viacyclocondensation reactions of pyrazolo-enaminone with a series of arylidenemalononitriles; compound 5 was obtained from 5-amino-4-cyanopyrazole. The structures of the target compounds were investigated by spectral techniques and elemental analysis (IR, UV–Vis, 1H NMR, 13C NMR and ESI-MS). All compounds were evaluated for their in vitro cytotoxicity employing a panel of different human tumor cell lines, A375, HT29, MCF7, A2780, FaDu as well as non-malignant NIH 3T3 and HEK293 cells. It has been found that the pyrazolo-pyrido-pyrimidine analog bearing a 4-Br-phenyl moiety was the most active toward many cell lines with EC50 values ranging between 9.1 and 13.5 µM. Moreover, in silico docking studies of the latter with six anticancer drug targets, i.e., DHFR, VEGFR2, HER-2/neu, hCA-IX, CDK6 and LOX5, were also performed, in order to gain some insights into their putative mode of binding interaction and to estimate the free binding energy of this bioactive molecule.

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“…Cells were harvested and protein was prepared as described previously (Aliwaini et al 2021). Primary antibodies used for western blotting are anti-p-Stat3 (sc-8059), anti-PARP1/2 (sc-7150), anti-caspase-9 (sc-56076), anti-p53 (sc-126), anti-p21 (sc-756) and anti-α-Tubulin (sc-8035) (Santa Cruz, California, USA).…”

Section: Western Blottingmentioning

confidence: 99%

“…Immunohistochemical analysis revealed that breast cancers that express the estrogen receptor, progesterone receptor or both respond well to hormone therapy (Aliwaini et al 2019;Porras et al 2021). Another important progress in breast cancer therapy was identifying and targeting the Her2 subtype of epidermal growth factor receptors (EGFR) which improved the outcome of Her2positive patients (Aliwaini et al 2021). Triple-negative breast cancers (TNBCs) are called such because they lack receptors for estrogen, progesterone, and Her2.…”

Section: Introductionmentioning

confidence: 99%

Synergistic anticancer effect of combination treatment of vitamin D and pitavastatin on the HCC1937 breast cancer cells

AlTawil¹,

Abdulla²,

Aliwaini

2022

J Exp Bio & Ag Sci

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Vitamin D (Vit D) has anticancer properties including activating cell senescence inhibiting cancer cell proliferation, inducing apoptotic cell death, and decreasing cancer cell migration. On the other hand, statins showed favorable anticancer activities including anti-survival, anti-proliferation, and anti-migration effects. The current study aimed to investigate the synergistic anticancer effect of Vit D and statins against HCC1937 triple-negative breast cancer cells. The antiproliferative effect was tested by MTT assay after 48 hours of the treatments. Trypan blue test and clonogenic assay were used to test the anti-survival activities of the treatments. The ability of the treatments to inhibit the migration ability was tested by scratch assay. Levels of the cell cycle and apoptotic markers were determined by western blotting. Results of the study revealed that all the tested compounds including Vit D, atorvastatin (Ator), simvastatin (Simv), and pitavastatin (Pita) inhibited HCC1937 breast cancer cell growth with different IC50 values ranging from 4.49-12.95 µM. Combined application of Pita and Vit D showed potent synergistic antiproliferative activities against HCC1937 breast cancer cells. The combined therapy of (1µM Vit D and 2 µM Pita) inhibited HCC1937 cell proliferation by cell cycle arrest and apoptosis as evidenced by increasing p21, p53, and cleaved PARP. Finally, the combined treatment decreased the p-STAT3 level in HCC1937 breast cancer cells. The results of the study can be concluded that the combined treatment of Pita and Vit D has a synergistic anticancer effect against HCC1937 breast cancer cells.

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Design, Synthesis and Biological Evaluation of Novel Pyrazolo[1,2,4]triazolopyrimidine Derivatives as Potential Anticancer Agents

Cited by 17 publications

References 43 publications

Molecular Docking Approach For Design and Synthesis of Thioxanthone Derivatives as Anticancer Agents

Molecular Docking Approach For Design and Synthesis of Thioxanthone Derivatives as Anticancer Agents

Synthesis and In Silico Docking of New Pyrazolo[4,3-e]pyrido[1,2-a]pyrimidine-based Cytotoxic Agents

Synergistic anticancer effect of combination treatment of vitamin D and pitavastatin on the HCC1937 breast cancer cells

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