Design, Synthesis, and Anticancer Screening for Repurposed Pyrazolo[3,4-d]pyrimidine Derivatives on Four Mammalian Cancer Cell Lines

Othman, Eman M.; Bekhit, Amany; Anany, Mohamed A.; Dandekar, Thomas; Ragab, Hanan M.; Wahid, Ahmed

doi:10.3390/molecules26102961

Cited by 9 publications

(7 citation statements)

References 40 publications

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“…Ki-67 is a nuclear protein that is associated with cellular proliferation. It was reported that chemotherapeutic agents caused decrease in its expression 58 .…”

Section: Discussionmentioning

confidence: 99%

Protective effects of hesperidin in cyclophosphamide-induced parotid toxicity in rats

Mostafa

Ibrahim

Borai

2023

Sci Rep

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Cyclophosphamide (CYP) is an alkylating agent that is used on a wide range as a treatment of malignancies and autoimmune diseases. Previous studies have shown the promising role of hesperidin (HSP) as an antioxidant agent against various models of toxic agents. The protective effect of the HSP against CYP-induced parotid damage was evaluated in this study. Forty rats (180–200 g) were divided into four equal groups: Group I (received normal saline), Group II (HSP-treated at a dose of 100 mg/kg/day for 7 consecutive days), Group III (CYP-treated at a dose of 200 mg/kg single intraperitoneal injection on the 7th day of the experiment), Group IV (CYP + HSP); HSP-treated at a dose of 100 mg/kg/day for 7 consecutive days and CYP (200 mg/kg) single intraperitoneal injection on the 7th day of the experiment. Afterwards, the oxidative stress and inflammatory markers, the histopathological and immunohistochemical alterations of the parotid tissues in the studied groups were evaluated. CYP intoxication induced a significant parotid tissue injury represented by the elevation in the values of malondialdehyde (MDA), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) and decrease in the catalase activity and glutathione peroxidase (GPx). Histologically, extensive histopathological alterations e.g., widely spaced serous acini with irregular shapes and congested blood vessels as well as downregulated ki-67 and alpha-smooth muscle actin (α-SMA) immunoexpression were induced by CYP. HSP administration markedly improved the biochemical and the histopathological studies. We can conclude that HSP elicited protective effects against the CYP-induced parotid toxicity.

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“…Ki-67 is a nuclear protein that is associated with cellular proliferation. It was reported that chemotherapeutic agents caused decrease in its expression 58 .…”

Section: Discussionmentioning

confidence: 99%

Protective effects of hesperidin in cyclophosphamide-induced parotid toxicity in rats

Mostafa

Ibrahim

Borai

2023

Sci Rep

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“…It is widely reported that several TK inhibitors exhibit anti-liver fibrotic activity [ 91 , 92 , 93 , 94 ]. Hence, we examined for the first time the hepatoprotective effect of three celecoxib structurally related derivatives that were reported as kinase inhibitors having antineoplastic activity [ 21 , 95 ].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, some pyrazole-based compounds have been reported to have antifibrotic potentials [ 17 , 18 , 19 ]. Among these, some new pyrazolo[3,4-d]pyrimidines were reported to suppress COX-2 expression at low concentrations [ 20 ], while others possessed antineoplastic activity and were reported as kinase inhibitors [ 21 ]. Consequently, such traits of new pyrazole-based compounds would serve as potential therapeutic candidates targeting HSCs to ameliorate liver fibrosis without being toxic to normal cells.…”

Section: Introductionmentioning

confidence: 99%

The Role of Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitors in The Attenuation of CCl4-Induced Liver Fibrosis in Rats

et al. 2023

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Liver Fibrosis can be life-threatening if left untreated as it may lead to serious, incurable complications. The common therapeutic approach is to reverse the fibrosis while the intervention is still applicable. Celecoxib was shown to exhibit some antifibrotic properties in the induced fibrotic liver in rats. The present study aimed to investigate the possible antifibrotic properties in CCl4-induced liver fibrosis in male Sprague–Dawley rats compared to celecoxib of three novel methoxylated pyrazolo[3,4-d]pyrimidines. The three newly synthesized compounds were proved to be safe candidates. They showed a therapeutic effect against severe CCl4-induced fibrosis but at different degrees. The three compounds were able to partially reverse hepatic architectural distortion and reduce the fibrotic severity by showing antioxidant properties reducing MDA with increasing GSH and SOD levels, remodeling the extracellular matrix proteins and liver enzymes balance, and reducing the level of proinflammatory (TNF-α and IL-6) and profibrogenic (TGF-β) cytokines. The results revealed that the dimethoxy-analog exhibited the greatest activity in all the previously mentioned parameters compared to celecoxib and the other two analogs which could be attributed to the different methoxylation patterns of the derivatives. Collectively, the dimethoxy-derivative could be considered a safe promising antifibrotic candidate.

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“…Inhibition of p53 protein function is correlated with the growth of liver cancer and poor prognosis (63). Ki67 has a remarkable value in providing evidence of prognostic value caused by tumor growth and proliferation (64). To investigate the correlation between gut microbiota and environmental factors, we evaluated AFP, p53, Ki67, CK19, Th/Ts, C3, and IgG.…”

Section: Discussionmentioning

confidence: 99%

Operable hepatitis B virus-related hepatocellular carcinoma: gut microbiota profile of patients at different ages

Peng¹,

Xu²,

Zeng³

et al. 2022

Ann Transl Med

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Background: Age was important prognostic factors for operable hepatocellular carcinoma patients. The aim of the present study was to assess the difference in gut microbiota in patients with operable hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) at different ages ; to investigate the features of the microbiota and its function associated with different ages; to provide a preliminary look at effects of the gut microbiota dimension on prognostic.Methods: From September 2020 to May 2021, patients with HBV-HCC were able to undergo liver resection and were recruited consecutively and divided into the younger age group (age <45 years) (Y.AG) (n=20), middle age group (age from 45 to 65 years) (M.AG) (n=13) 45-65 years, and older age group (age >65 years) (O.AG) (n=20). The relationships between gut microbiota and different ages were explored using 16S rRNA gene sequencing data. PICRUST2 was used to examine the metagenomic data in PHLF patients.Fisher's exact and Mann-Whitney U-test were used for the data analysis.Results: Pairwise comparison between the three groups showed that the α-diversity of Y.AG was significantly higher than that of O.AG (ACE Index, P=0.017; chao1 Index, P=0.031; observed_species Index, P=0.011; and goods_coverage Index, P=0.041). The β-diversity in the 3 groups differed significantly (stress =0.100), while the composition (β-diversity) differed significantly between the Y.AG and the M.AG (stress =0.090), the M.AG and the O.AG (stress =0.095), and the Y.AG and the O.AG (stress =0.099). At the genus level, 7 bacterial genera were significantly enriched in the O.AG compared with the Y.AG, of which Streptococcus, Blautia, Erysipelotrichaceae_UCG-003, and Fusicatenibacter represented the major variances in O.AG microbiomes. Eleven genera were significantly increased in the O.AG, of which Prevotella, Allorhizobium-Neorhizobium-Pararhizobium-Rhizobium, Ruminiclostridium, and Phascolarctobacterium represented the major variances in the O.AG. The Y.AG and the O.AG were predicted by PICRUSt2 analysis, which found 72 pathways related to differential gut microbiome at the genus level. Redundancy analysis showed that 7 environmental factors were significantly correlated with intestinal microorganisms, especially in the Y.AG compared with the O.AG. Conclusions: Analysis of gut microbiota characteristics in patients of different ages could ultimately contribute to the development of novel avenues for the treatment of HCC at different ages.

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Design, Synthesis, and Anticancer Screening for Repurposed Pyrazolo[3,4-d]pyrimidine Derivatives on Four Mammalian Cancer Cell Lines

Cited by 9 publications

References 40 publications

Protective effects of hesperidin in cyclophosphamide-induced parotid toxicity in rats

Protective effects of hesperidin in cyclophosphamide-induced parotid toxicity in rats

The Role of Pyrazolo[3,4-d]pyrimidine-Based Kinase Inhibitors in The Attenuation of CCl4-Induced Liver Fibrosis in Rats

Operable hepatitis B virus-related hepatocellular carcinoma: gut microbiota profile of patients at different ages

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