This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Design and synthesis of a new series of benzofuran derivatives has been performed. 1 H-NMR, 13 C-... more Design and synthesis of a new series of benzofuran derivatives has been performed. 1 H-NMR, 13 C-NMR, elemental analysis, and IR were used to confirm the structures of the produced compounds. Hepatocellular carcinoma (HePG2), mammary gland breast cancer (MCF-7), epithelioid carcinoma cervical cancer (Hela), and human prostate cancer are used to test anticancer activity (PC3). In compared to DOX (4.17-8.87 µM), Compound 8 demonstrated the highest activity against HePG and PC3 cell lines, with an IC 50 range of 11-17 µM. Compound 8 inhibited PI3K and VEGFR-2 with IC 50 values of 2.21 and 68 nM, respectively, compared to 6.18 nM for compound LY294002 and 31.2 nM for compound sorafenib as PI3K and VEGFR-2 reference inhibitors, selectively. The molecular docking and binding affinity of the generated compounds were estimated and studied computationally utilizing molecular operating environment software as a PI3K and VEGFR-2 inhibitor (MOE). In conclusion, compound 8 exhibited significant action against hepatocellular and cervical cancer cell lines. Mechanistic study showed that it had a dual inhibitory effect against PI3K and VEGFR-2. Cancer is firstly reported in Ancient Egypt in the Ebers papyrus which is an Egyptian medical papyrus that was written approximately 1550 BC 1. Until the nineteenth century, it was considered as an incurable disease 2. By the end of 2021, the American Cancer Society anticipates that around 2 million new cancer cases with 600,000 deaths will occur in the United States 3. Phosphatidylinositol-3-kinases (PI3K) are important enzymes that control a variety of physiological processes and have a critical role in apoptosis 4,5. In tumor tissue and various respiratory inflammations, it is considerably overexpressed 6. Many malignancies have abnormal PI3K activation, and increased activity also indicates cancer therapy resistance. Unregulated signaling of cancer cells can be caused by a variety of factors, including mutations, tyrosine kinase amplification, or PI3K itself 7,8. PI3K signaling causes the growth factor to attach to the tyrosine kinase receptor, causing receptor dimerization. As a result, at the internal docking site, the lipid kinase PI3K is activated and initiated. The membrane lipid phosphatidylinositol 4.5-bisphosphate 2 (pip2) is then transformed by PI3K into phosphatidylinositol 4,5-bisphosphate 3 (pip3), an active form of pip2, resulting in the stimulation of the important signaling enzyme protein kinase B (AKT) 9. AKT promotes cell growth by increasing protein synthesis, which is aided by mTOR signals, and lowers cell death by inhibiting the fork head box o family of proteins (FOXO). They are widely expressed in cells and function to integrate a variety of growth factors, oxidative stress signals, and other stimulatory signals. PI3K indirectly inhibit FOXO which leads to inhibition of apoptosis 8,10. Angiogenesis, or the formation of a new vessel from an existing one, is a crucial part of tumor cell proliferation. The angiogenesis process is aided by the presence of VEGF and its receptor (VEGFR). Inhibition of VEGFR is thought to be one of the most promising cancer therapeutic targets 11. Compared to VEGFR-1 and VEGFR-3, VEGFR-2 has more kinase activity. In VEGF endothelial cells, this receptor is a response controller. These restrictions include permeability, proliferation, invasion, and migration 12. VEGFR inhibitors frequently face the challenge of developing of resistance to new therapeutic drugs after a period of treatment, even though antiangiogenetic has proven to be a promising method for cancer therapy.
This study deals with synthesis of a new set of benzofuran and 5H-furo[3,2-g]chromone linked vari... more This study deals with synthesis of a new set of benzofuran and 5H-furo[3,2-g]chromone linked various heterocyclic functionalities using concise synthetic approaches aiming to gain new antiproliferative candidates against MCF-7 breast cancer cells of p38α MAP kinase inhibiting activity. The biological data proved the significant sensitivity of breast cancer cell lines MCF-7 towards most of the prepared compounds in comparison with doxorubicin. In addition, compounds IIa,b, Va,b, VIa,b, VIIa,b, VIIIa,b, XIc showed significant in vitro p38α MAPK inhibiting potency comparable to the reference standard SB203580. Cell cycle analysis and apoptosis detection data demonstrated that compound VIa induced G2/M phase arrest and apoptosis in MCF-7 cancer cells, in addition to its activation of the caspases-9 and -3. Gold molecular docking studies rationalized the highly acceptable correlation between the calculated docking scores of fitness and the biological data of p38α MAP kinase inhibition. T...
Acute respiratory distress syndrome (ARDS) is recognized to be accompanied by severe lung and hea... more Acute respiratory distress syndrome (ARDS) is recognized to be accompanied by severe lung and heart complications. This study aimed to demonstrate the efficacy of Calcium hypochlorite in cyclophosphamide (CP)induced pulmonary and cardiac injury in mice. The CP-induced toxicity in the lung and heart is like that caused by ARDS. Calcium hypochlorite significantly attenuated doth lung and heart functionality and significantly reduced the CP-induced perivascular inflammation, congestion of blood vessels, and severe morphological changes of the alveolar wall. It also exerts anti-inflammatory and antioxidant effects on CP-induced pulmonary and heart toxicity. Given these results, calcium hypochlorite successfully ameliorates ARDS symptoms rendering calcium hypochlorite to be a promising agent to be tested in models of pneumonia caused by bacterial or viral infections, including those of acute respiratory distress syndrome (ARDS).
A new series of benzofuran derivatives has been designed and synthesized. The structures of the s... more A new series of benzofuran derivatives has been designed and synthesized. The structures of the synthesized compounds have been confirmed by the use of 1H NMR, 13C NMR, 2D 1H-1H NOESY NMR, and IR. Anticancer activity is evaluated against Hepatocellular carcinoma (HePG2), mammary gland breast cancer (MCF-7), Epitheliod carcinoma cervix cancer (Hela) and human prostate cancer (PC3). Compounds 8, 9, and 11 showed the highest activity towards the four cell lines with an IC50 range of 8.49-16.72 µM, 6.55-13.14 µM and 4-8.99 µM respectively in comparison to DOX (4.17-8.87 µM). Phosphatidylinositol-3-kinases (PI3K) inhibition was evaluated against the most active anticancer compounds 8, 9 and 11. Compounds 8, 9 and 11 showed good inhibitory activity against PI3Kα with IC50 values 4.1, 7.8, and 20.5 µM, respectively in comparison to 6.18 µM for the reference compound LY294002. In addition, activity of compounds 8 and 9 on cell cycle arrest and induction of apoptosis in different phases of M...
Canadian Journal of Physiology and Pharmacology, 2016
Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of med... more Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of medical practice. Sodium valproate (VPA) is among many drugs with reported hepatotoxic effects. Sulforaphane (SFN) is a thiol compound found in wide abundance in cruciferous plants that has numerous reported therapeutic efficacies. The current investigation sheds light on the potential hepatoprotective effect of SFN against VPA-induced liver injury in rats. Twice daily VPA (700 mg/kg, i.p.) for 7 days induced significant biochemical alterations and hepatic histopathological damage. SFN (0.5 mg/kg, orally) for 7 days significantly boosted liver function biomarkers; it reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase, and restored serum albumin concentration in a significant manner. Meanwhile, SFN significantly mitigated VPA-induced histopathological alterations. To highlight the mechanisms implicated in the observed hepatoprotective action, hepatic mal...
Canadian Journal of Physiology and Pharmacology, 2016
Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of med... more Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of medical practice. Sodium valproate (VPA) is among many drugs with reported hepatotoxic effects. Sulforaphane (SFN) is a thiol compound found in wide abundance in cruciferous plants that has numerous reported therapeutic efficacies. The current investigation sheds light on the potential hepatoprotective effect of SFN against VPA-induced liver injury in rats. Twice daily VPA (700 mg/kg, i.p.) for 7 days induced significant biochemical alterations and hepatic histopathological damage. SFN (0.5 mg/kg, orally) for 7 days significantly boosted liver function biomarkers; it reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase, and restored serum albumin concentration in a significant manner. Meanwhile, SFN significantly mitigated VPA-induced histopathological alterations. To highlight the mechanisms implicated in the observed hepatoprotective action, hepatic mal...
Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of med... more Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of medical practice. Sodium valproate (VPA) is among many drugs with reported hepatotoxic effects. Sulforaphane (SFN) is a thiol compound found in wide abundance in cruciferous plants that has numerous reported therapeutic efficacies. The current investigation sheds light on the potential hepatoprotective effect of SFN against VPA-induced liver injury in rats. Twice daily VPA (700 mg/kg, i.p.) for 7 days induced significant biochemical alterations and hepatic histopathological damage. SFN (0.5 mg/kg, orally) for 7 days significantly boosted liver function biomarkers; it reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase, and restored serum albumin concentration in a significant manner. Meanwhile, SFN significantly mitigated VPA-induced histopathological alterations. To highlight the mechanisms implicated in the observed hepatoprotective action, hepatic malondialdehyde and tumour necrosis factor ␣ content significantly declined with concomitant increase in hepatic heme oxygenase-1 content and glutathione concentration with SFN treatment. In conclusion, SFN can significantly ameliorate VPA-induced hepatotoxicity and liver injury primarily by direct association between antioxidant and anti-inflammatory properties. Résumé : L'hépatotoxicité médicamenteuse est l'un des principaux enjeux auxquels doit faire face la pratique médicale. Le valproate de sodium (VPA) est l'un des nombreux médicaments pour lesquels on signale des effets hépatotoxiques. Le sul-foraphane (SFN) est un composé thiol que l'on trouve en grande abondance dans les plantes crucifères avec un grand nombre d'actions thérapeutiques rapportées. Les présentes recherches mettent en lumière les éventuels effets hépatoprotecteurs du SFN contre les lésions hépatiques provoquées par le VPA chez le rat. L'administration biquotidienne de VPA (à 700 mg/kg) par voie i.p. pendant 7 jours provoquait des modifications biochimiques importantes et des dommages hépatiques à l'histopathologie. Le SFN (à 0,5 mg/kg, par voie orale) pendant 7 jours stimulait la production de biomarqueurs de la fonction hépatique de façon marquée : réduction de l'activité sérique de l'alanine aminotransférase, de l'aspartate aminotransférase et des taux de phosphatase alcaline ainsi que net rétablissement des concentrations sériques d'albumine. En même temps, le SFN atténuait nettement les changements histopathologiques provoqués par le VPA. Fait qui met en évidence les mécanismes jouant un rôle dans les actions hépatoprotectrices observées, sous l'effet du SFN, les concentrations hépatiques de malondialdéhyde et de facteur de nécrose tumorale ␣ diminuaient de façon marquée en tandem avec une augmentation des concentrations hépatiques d'hème oxygénase 1 (HO-1) et des taux de glutathion. En conclusion, principalement par l'association directe de propriétés antioxydantes et anti-inflammatoires, le SFN permet d'atténuer nettement l'hépatotoxicité et les lésions hépatiques provoquées par le VPA. [Traduit par la Rédaction] Mots-clés : lésions hépatiques, valproate de sodium, sulforaphane, TNF␣, hème oxygénase 1.
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Design and synthesis of a new series of benzofuran derivatives has been performed. 1 H-NMR, 13 C-... more Design and synthesis of a new series of benzofuran derivatives has been performed. 1 H-NMR, 13 C-NMR, elemental analysis, and IR were used to confirm the structures of the produced compounds. Hepatocellular carcinoma (HePG2), mammary gland breast cancer (MCF-7), epithelioid carcinoma cervical cancer (Hela), and human prostate cancer are used to test anticancer activity (PC3). In compared to DOX (4.17-8.87 µM), Compound 8 demonstrated the highest activity against HePG and PC3 cell lines, with an IC 50 range of 11-17 µM. Compound 8 inhibited PI3K and VEGFR-2 with IC 50 values of 2.21 and 68 nM, respectively, compared to 6.18 nM for compound LY294002 and 31.2 nM for compound sorafenib as PI3K and VEGFR-2 reference inhibitors, selectively. The molecular docking and binding affinity of the generated compounds were estimated and studied computationally utilizing molecular operating environment software as a PI3K and VEGFR-2 inhibitor (MOE). In conclusion, compound 8 exhibited significant action against hepatocellular and cervical cancer cell lines. Mechanistic study showed that it had a dual inhibitory effect against PI3K and VEGFR-2. Cancer is firstly reported in Ancient Egypt in the Ebers papyrus which is an Egyptian medical papyrus that was written approximately 1550 BC 1. Until the nineteenth century, it was considered as an incurable disease 2. By the end of 2021, the American Cancer Society anticipates that around 2 million new cancer cases with 600,000 deaths will occur in the United States 3. Phosphatidylinositol-3-kinases (PI3K) are important enzymes that control a variety of physiological processes and have a critical role in apoptosis 4,5. In tumor tissue and various respiratory inflammations, it is considerably overexpressed 6. Many malignancies have abnormal PI3K activation, and increased activity also indicates cancer therapy resistance. Unregulated signaling of cancer cells can be caused by a variety of factors, including mutations, tyrosine kinase amplification, or PI3K itself 7,8. PI3K signaling causes the growth factor to attach to the tyrosine kinase receptor, causing receptor dimerization. As a result, at the internal docking site, the lipid kinase PI3K is activated and initiated. The membrane lipid phosphatidylinositol 4.5-bisphosphate 2 (pip2) is then transformed by PI3K into phosphatidylinositol 4,5-bisphosphate 3 (pip3), an active form of pip2, resulting in the stimulation of the important signaling enzyme protein kinase B (AKT) 9. AKT promotes cell growth by increasing protein synthesis, which is aided by mTOR signals, and lowers cell death by inhibiting the fork head box o family of proteins (FOXO). They are widely expressed in cells and function to integrate a variety of growth factors, oxidative stress signals, and other stimulatory signals. PI3K indirectly inhibit FOXO which leads to inhibition of apoptosis 8,10. Angiogenesis, or the formation of a new vessel from an existing one, is a crucial part of tumor cell proliferation. The angiogenesis process is aided by the presence of VEGF and its receptor (VEGFR). Inhibition of VEGFR is thought to be one of the most promising cancer therapeutic targets 11. Compared to VEGFR-1 and VEGFR-3, VEGFR-2 has more kinase activity. In VEGF endothelial cells, this receptor is a response controller. These restrictions include permeability, proliferation, invasion, and migration 12. VEGFR inhibitors frequently face the challenge of developing of resistance to new therapeutic drugs after a period of treatment, even though antiangiogenetic has proven to be a promising method for cancer therapy.
This study deals with synthesis of a new set of benzofuran and 5H-furo[3,2-g]chromone linked vari... more This study deals with synthesis of a new set of benzofuran and 5H-furo[3,2-g]chromone linked various heterocyclic functionalities using concise synthetic approaches aiming to gain new antiproliferative candidates against MCF-7 breast cancer cells of p38α MAP kinase inhibiting activity. The biological data proved the significant sensitivity of breast cancer cell lines MCF-7 towards most of the prepared compounds in comparison with doxorubicin. In addition, compounds IIa,b, Va,b, VIa,b, VIIa,b, VIIIa,b, XIc showed significant in vitro p38α MAPK inhibiting potency comparable to the reference standard SB203580. Cell cycle analysis and apoptosis detection data demonstrated that compound VIa induced G2/M phase arrest and apoptosis in MCF-7 cancer cells, in addition to its activation of the caspases-9 and -3. Gold molecular docking studies rationalized the highly acceptable correlation between the calculated docking scores of fitness and the biological data of p38α MAP kinase inhibition. T...
Acute respiratory distress syndrome (ARDS) is recognized to be accompanied by severe lung and hea... more Acute respiratory distress syndrome (ARDS) is recognized to be accompanied by severe lung and heart complications. This study aimed to demonstrate the efficacy of Calcium hypochlorite in cyclophosphamide (CP)induced pulmonary and cardiac injury in mice. The CP-induced toxicity in the lung and heart is like that caused by ARDS. Calcium hypochlorite significantly attenuated doth lung and heart functionality and significantly reduced the CP-induced perivascular inflammation, congestion of blood vessels, and severe morphological changes of the alveolar wall. It also exerts anti-inflammatory and antioxidant effects on CP-induced pulmonary and heart toxicity. Given these results, calcium hypochlorite successfully ameliorates ARDS symptoms rendering calcium hypochlorite to be a promising agent to be tested in models of pneumonia caused by bacterial or viral infections, including those of acute respiratory distress syndrome (ARDS).
A new series of benzofuran derivatives has been designed and synthesized. The structures of the s... more A new series of benzofuran derivatives has been designed and synthesized. The structures of the synthesized compounds have been confirmed by the use of 1H NMR, 13C NMR, 2D 1H-1H NOESY NMR, and IR. Anticancer activity is evaluated against Hepatocellular carcinoma (HePG2), mammary gland breast cancer (MCF-7), Epitheliod carcinoma cervix cancer (Hela) and human prostate cancer (PC3). Compounds 8, 9, and 11 showed the highest activity towards the four cell lines with an IC50 range of 8.49-16.72 µM, 6.55-13.14 µM and 4-8.99 µM respectively in comparison to DOX (4.17-8.87 µM). Phosphatidylinositol-3-kinases (PI3K) inhibition was evaluated against the most active anticancer compounds 8, 9 and 11. Compounds 8, 9 and 11 showed good inhibitory activity against PI3Kα with IC50 values 4.1, 7.8, and 20.5 µM, respectively in comparison to 6.18 µM for the reference compound LY294002. In addition, activity of compounds 8 and 9 on cell cycle arrest and induction of apoptosis in different phases of M...
Canadian Journal of Physiology and Pharmacology, 2016
Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of med... more Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of medical practice. Sodium valproate (VPA) is among many drugs with reported hepatotoxic effects. Sulforaphane (SFN) is a thiol compound found in wide abundance in cruciferous plants that has numerous reported therapeutic efficacies. The current investigation sheds light on the potential hepatoprotective effect of SFN against VPA-induced liver injury in rats. Twice daily VPA (700 mg/kg, i.p.) for 7 days induced significant biochemical alterations and hepatic histopathological damage. SFN (0.5 mg/kg, orally) for 7 days significantly boosted liver function biomarkers; it reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase, and restored serum albumin concentration in a significant manner. Meanwhile, SFN significantly mitigated VPA-induced histopathological alterations. To highlight the mechanisms implicated in the observed hepatoprotective action, hepatic mal...
Canadian Journal of Physiology and Pharmacology, 2016
Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of med... more Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of medical practice. Sodium valproate (VPA) is among many drugs with reported hepatotoxic effects. Sulforaphane (SFN) is a thiol compound found in wide abundance in cruciferous plants that has numerous reported therapeutic efficacies. The current investigation sheds light on the potential hepatoprotective effect of SFN against VPA-induced liver injury in rats. Twice daily VPA (700 mg/kg, i.p.) for 7 days induced significant biochemical alterations and hepatic histopathological damage. SFN (0.5 mg/kg, orally) for 7 days significantly boosted liver function biomarkers; it reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase, and restored serum albumin concentration in a significant manner. Meanwhile, SFN significantly mitigated VPA-induced histopathological alterations. To highlight the mechanisms implicated in the observed hepatoprotective action, hepatic mal...
Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of med... more Drug-induced hepatotoxicity is one of the most commonly encountered obstacles in the field of medical practice. Sodium valproate (VPA) is among many drugs with reported hepatotoxic effects. Sulforaphane (SFN) is a thiol compound found in wide abundance in cruciferous plants that has numerous reported therapeutic efficacies. The current investigation sheds light on the potential hepatoprotective effect of SFN against VPA-induced liver injury in rats. Twice daily VPA (700 mg/kg, i.p.) for 7 days induced significant biochemical alterations and hepatic histopathological damage. SFN (0.5 mg/kg, orally) for 7 days significantly boosted liver function biomarkers; it reduced serum alanine transaminase, aspartate aminotransferase, and alkaline phosphatase, and restored serum albumin concentration in a significant manner. Meanwhile, SFN significantly mitigated VPA-induced histopathological alterations. To highlight the mechanisms implicated in the observed hepatoprotective action, hepatic malondialdehyde and tumour necrosis factor ␣ content significantly declined with concomitant increase in hepatic heme oxygenase-1 content and glutathione concentration with SFN treatment. In conclusion, SFN can significantly ameliorate VPA-induced hepatotoxicity and liver injury primarily by direct association between antioxidant and anti-inflammatory properties. Résumé : L'hépatotoxicité médicamenteuse est l'un des principaux enjeux auxquels doit faire face la pratique médicale. Le valproate de sodium (VPA) est l'un des nombreux médicaments pour lesquels on signale des effets hépatotoxiques. Le sul-foraphane (SFN) est un composé thiol que l'on trouve en grande abondance dans les plantes crucifères avec un grand nombre d'actions thérapeutiques rapportées. Les présentes recherches mettent en lumière les éventuels effets hépatoprotecteurs du SFN contre les lésions hépatiques provoquées par le VPA chez le rat. L'administration biquotidienne de VPA (à 700 mg/kg) par voie i.p. pendant 7 jours provoquait des modifications biochimiques importantes et des dommages hépatiques à l'histopathologie. Le SFN (à 0,5 mg/kg, par voie orale) pendant 7 jours stimulait la production de biomarqueurs de la fonction hépatique de façon marquée : réduction de l'activité sérique de l'alanine aminotransférase, de l'aspartate aminotransférase et des taux de phosphatase alcaline ainsi que net rétablissement des concentrations sériques d'albumine. En même temps, le SFN atténuait nettement les changements histopathologiques provoqués par le VPA. Fait qui met en évidence les mécanismes jouant un rôle dans les actions hépatoprotectrices observées, sous l'effet du SFN, les concentrations hépatiques de malondialdéhyde et de facteur de nécrose tumorale ␣ diminuaient de façon marquée en tandem avec une augmentation des concentrations hépatiques d'hème oxygénase 1 (HO-1) et des taux de glutathion. En conclusion, principalement par l'association directe de propriétés antioxydantes et anti-inflammatoires, le SFN permet d'atténuer nettement l'hépatotoxicité et les lésions hépatiques provoquées par le VPA. [Traduit par la Rédaction] Mots-clés : lésions hépatiques, valproate de sodium, sulforaphane, TNF␣, hème oxygénase 1.
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