Unveiling the antitumor potential of novel N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamides as dual inhibitors of VEGFR2 kinase and cytochrome P450 for targeted treatment of hepatocellular carcinoma
Being the sixth most diagnosed cancer and the fourth leading cause of cancer-related deaths worldwide, liver cancer is considered as a serious disease with a high prevalence and poor prognosis. Current anticancer drugs for liver cancer have drawbacks, such as limited efficacy in later stages of the...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-08-01
|
| Series: | Frontiers in Chemistry |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fchem.2023.1231030/full |
| _version_ | 1797754638138605568 |
|---|---|
| author | Eman M. Radwan Eman Abo-Elabass Atef E. Abd El-Baky Hussah Abdullah Alshwyeh Hussah Abdullah Alshwyeh Riyad A. Almaimani Ghassan Almaimani Ibrahim Abdel Aziz Ibrahim Abdulaziz Albogami Mariusz Jaremko Samar Z. Alshawwa Essa M. Saied Essa M. Saied |
| author_facet | Eman M. Radwan Eman Abo-Elabass Atef E. Abd El-Baky Hussah Abdullah Alshwyeh Hussah Abdullah Alshwyeh Riyad A. Almaimani Ghassan Almaimani Ibrahim Abdel Aziz Ibrahim Abdulaziz Albogami Mariusz Jaremko Samar Z. Alshawwa Essa M. Saied Essa M. Saied |
| author_sort | Eman M. Radwan |
| collection | DOAJ |
| description | Being the sixth most diagnosed cancer and the fourth leading cause of cancer-related deaths worldwide, liver cancer is considered as a serious disease with a high prevalence and poor prognosis. Current anticancer drugs for liver cancer have drawbacks, such as limited efficacy in later stages of the disease, toxicity to healthy cells, and the potential for drug resistance. There is ample evidence that coumarin-based compounds are potent anticancer agents, with numerous analogues currently being investigated in preclinical and clinical studies. The current study aimed to explore the antitumor potency of a new class of 8-methoxycoumarin-3-carboxamides against liver cancer. Toward this aim, we have designed, synthesized, and characterized a new set of N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamide analogues. The assessment of antitumor activity revealed that the synthesized class of compounds possesses substantial cytotoxicity toward Hep-G2 cells when compared to staurosporine, without significant impact on normal cells. Out of the synthesized compounds, compound 7 demonstrated the most potent cytotoxic effect against Hep-G2 cells with an IC50 of 0.75 µM, which was more potent than the drug staurosporine (IC50 = 8.37 µM). The investigation into the mechanism behind the antiproliferative activity of compound 7 revealed that it interferes with DNA replication and induces DNA damage, leading to cell cycle arrest as demonstrated by a significant decrease in the percentage of cells in the G1 and G2/M phases, along with an increase in the percentage of cells in the S phase. Flow cytometric analysis further revealed that compound 7 has the ability to trigger programmed cell death by inducing necrosis and apoptosis in HepG-2 cells. Further explorations into the mechanism of action demonstrated that compound 7 displays a potent dual-inhibitory activity toward cytochrome P450 and vascular endothelial growth factor receptor-2 (VEGFR-2) proteins, as compared to sorafenib drug. Further, detailed computational studies revealed that compound 7 displays a considerable binding affinity toward the binding cavity of VEGFR2 and CYP450 proteins. Taken together, our findings indicate that the newly synthesized class of compounds, particularly compound 7, could serve as a promising scaffold for the development of highly effective anticancer agents against liver cancer. |
| first_indexed | 2024-03-12T17:35:18Z |
| format | Article |
| id | doaj.art-26a6c1668e4f4501bf14d01c0495212b |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-03-12T17:35:18Z |
| publishDate | 2023-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Chemistry |
| spelling | doaj.art-26a6c1668e4f4501bf14d01c0495212b2023-08-04T11:18:52ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462023-08-011110.3389/fchem.2023.12310301231030Unveiling the antitumor potential of novel N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamides as dual inhibitors of VEGFR2 kinase and cytochrome P450 for targeted treatment of hepatocellular carcinomaEman M. Radwan0Eman Abo-Elabass1Atef E. Abd El-Baky2Hussah Abdullah Alshwyeh3Hussah Abdullah Alshwyeh4Riyad A. Almaimani5Ghassan Almaimani6Ibrahim Abdel Aziz Ibrahim7Abdulaziz Albogami8Mariusz Jaremko9Samar Z. Alshawwa10Essa M. Saied11Essa M. Saied12The Division of Organic Chemistry, Chemistry Department, Faculty of Science, Port-Said University, Port-Said, EgyptThe Division of Biochemistry, Chemistry Department, Faculty of Science, Port-Said University, Port-Said, EgyptBiochemistry Department, Faculty of Pharmacy, Port-Said University, Port-Said, EgyptDepartment of Biology, College of Science, Imam Abdulrahman Bin Faisal University, Dammam, Saudi ArabiaBasic and Applied Scientific Research Centre, Imam Abdulrahman Bin Faisal University, Dammam, Saudi ArabiaDepartment of Biochemistry, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi ArabiaDepartment of Surgery, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi ArabiaDepartment of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi ArabiaBiology Department, Faculty of science, Al-Baha University, Al Aqiq, Saudi Arabia0Division of Biological and Environmental Sciences (BESE) and Engineering, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia1Department of Pharmaceutical Sciences, College of Pharmacy, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia2Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, Egypt3Institute for Chemistry, Humboldt Universität zu Berlin, Berlin, GermanyBeing the sixth most diagnosed cancer and the fourth leading cause of cancer-related deaths worldwide, liver cancer is considered as a serious disease with a high prevalence and poor prognosis. Current anticancer drugs for liver cancer have drawbacks, such as limited efficacy in later stages of the disease, toxicity to healthy cells, and the potential for drug resistance. There is ample evidence that coumarin-based compounds are potent anticancer agents, with numerous analogues currently being investigated in preclinical and clinical studies. The current study aimed to explore the antitumor potency of a new class of 8-methoxycoumarin-3-carboxamides against liver cancer. Toward this aim, we have designed, synthesized, and characterized a new set of N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamide analogues. The assessment of antitumor activity revealed that the synthesized class of compounds possesses substantial cytotoxicity toward Hep-G2 cells when compared to staurosporine, without significant impact on normal cells. Out of the synthesized compounds, compound 7 demonstrated the most potent cytotoxic effect against Hep-G2 cells with an IC50 of 0.75 µM, which was more potent than the drug staurosporine (IC50 = 8.37 µM). The investigation into the mechanism behind the antiproliferative activity of compound 7 revealed that it interferes with DNA replication and induces DNA damage, leading to cell cycle arrest as demonstrated by a significant decrease in the percentage of cells in the G1 and G2/M phases, along with an increase in the percentage of cells in the S phase. Flow cytometric analysis further revealed that compound 7 has the ability to trigger programmed cell death by inducing necrosis and apoptosis in HepG-2 cells. Further explorations into the mechanism of action demonstrated that compound 7 displays a potent dual-inhibitory activity toward cytochrome P450 and vascular endothelial growth factor receptor-2 (VEGFR-2) proteins, as compared to sorafenib drug. Further, detailed computational studies revealed that compound 7 displays a considerable binding affinity toward the binding cavity of VEGFR2 and CYP450 proteins. Taken together, our findings indicate that the newly synthesized class of compounds, particularly compound 7, could serve as a promising scaffold for the development of highly effective anticancer agents against liver cancer.https://www.frontiersin.org/articles/10.3389/fchem.2023.1231030/fullcoumarinhepatocellular carcinomacytotoxicitycell arrestapoptosiscytochrome P450 |
| spellingShingle | Eman M. Radwan Eman Abo-Elabass Atef E. Abd El-Baky Hussah Abdullah Alshwyeh Hussah Abdullah Alshwyeh Riyad A. Almaimani Ghassan Almaimani Ibrahim Abdel Aziz Ibrahim Abdulaziz Albogami Mariusz Jaremko Samar Z. Alshawwa Essa M. Saied Essa M. Saied Unveiling the antitumor potential of novel N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamides as dual inhibitors of VEGFR2 kinase and cytochrome P450 for targeted treatment of hepatocellular carcinoma Frontiers in Chemistry coumarin hepatocellular carcinoma cytotoxicity cell arrest apoptosis cytochrome P450 |
| title | Unveiling the antitumor potential of novel N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamides as dual inhibitors of VEGFR2 kinase and cytochrome P450 for targeted treatment of hepatocellular carcinoma |
| title_full | Unveiling the antitumor potential of novel N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamides as dual inhibitors of VEGFR2 kinase and cytochrome P450 for targeted treatment of hepatocellular carcinoma |
| title_fullStr | Unveiling the antitumor potential of novel N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamides as dual inhibitors of VEGFR2 kinase and cytochrome P450 for targeted treatment of hepatocellular carcinoma |
| title_full_unstemmed | Unveiling the antitumor potential of novel N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamides as dual inhibitors of VEGFR2 kinase and cytochrome P450 for targeted treatment of hepatocellular carcinoma |
| title_short | Unveiling the antitumor potential of novel N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamides as dual inhibitors of VEGFR2 kinase and cytochrome P450 for targeted treatment of hepatocellular carcinoma |
| title_sort | unveiling the antitumor potential of novel n substituted phenyl 8 methoxycoumarin 3 carboxamides as dual inhibitors of vegfr2 kinase and cytochrome p450 for targeted treatment of hepatocellular carcinoma |
| topic | coumarin hepatocellular carcinoma cytotoxicity cell arrest apoptosis cytochrome P450 |
| url | https://www.frontiersin.org/articles/10.3389/fchem.2023.1231030/full |
| work_keys_str_mv | AT emanmradwan unveilingtheantitumorpotentialofnovelnsubstitutedphenyl8methoxycoumarin3carboxamidesasdualinhibitorsofvegfr2kinaseandcytochromep450fortargetedtreatmentofhepatocellularcarcinoma AT emanaboelabass unveilingtheantitumorpotentialofnovelnsubstitutedphenyl8methoxycoumarin3carboxamidesasdualinhibitorsofvegfr2kinaseandcytochromep450fortargetedtreatmentofhepatocellularcarcinoma AT atefeabdelbaky unveilingtheantitumorpotentialofnovelnsubstitutedphenyl8methoxycoumarin3carboxamidesasdualinhibitorsofvegfr2kinaseandcytochromep450fortargetedtreatmentofhepatocellularcarcinoma AT hussahabdullahalshwyeh unveilingtheantitumorpotentialofnovelnsubstitutedphenyl8methoxycoumarin3carboxamidesasdualinhibitorsofvegfr2kinaseandcytochromep450fortargetedtreatmentofhepatocellularcarcinoma AT hussahabdullahalshwyeh unveilingtheantitumorpotentialofnovelnsubstitutedphenyl8methoxycoumarin3carboxamidesasdualinhibitorsofvegfr2kinaseandcytochromep450fortargetedtreatmentofhepatocellularcarcinoma AT riyadaalmaimani unveilingtheantitumorpotentialofnovelnsubstitutedphenyl8methoxycoumarin3carboxamidesasdualinhibitorsofvegfr2kinaseandcytochromep450fortargetedtreatmentofhepatocellularcarcinoma AT ghassanalmaimani unveilingtheantitumorpotentialofnovelnsubstitutedphenyl8methoxycoumarin3carboxamidesasdualinhibitorsofvegfr2kinaseandcytochromep450fortargetedtreatmentofhepatocellularcarcinoma AT ibrahimabdelazizibrahim unveilingtheantitumorpotentialofnovelnsubstitutedphenyl8methoxycoumarin3carboxamidesasdualinhibitorsofvegfr2kinaseandcytochromep450fortargetedtreatmentofhepatocellularcarcinoma AT abdulazizalbogami unveilingtheantitumorpotentialofnovelnsubstitutedphenyl8methoxycoumarin3carboxamidesasdualinhibitorsofvegfr2kinaseandcytochromep450fortargetedtreatmentofhepatocellularcarcinoma AT mariuszjaremko unveilingtheantitumorpotentialofnovelnsubstitutedphenyl8methoxycoumarin3carboxamidesasdualinhibitorsofvegfr2kinaseandcytochromep450fortargetedtreatmentofhepatocellularcarcinoma AT samarzalshawwa unveilingtheantitumorpotentialofnovelnsubstitutedphenyl8methoxycoumarin3carboxamidesasdualinhibitorsofvegfr2kinaseandcytochromep450fortargetedtreatmentofhepatocellularcarcinoma AT essamsaied unveilingtheantitumorpotentialofnovelnsubstitutedphenyl8methoxycoumarin3carboxamidesasdualinhibitorsofvegfr2kinaseandcytochromep450fortargetedtreatmentofhepatocellularcarcinoma AT essamsaied unveilingtheantitumorpotentialofnovelnsubstitutedphenyl8methoxycoumarin3carboxamidesasdualinhibitorsofvegfr2kinaseandcytochromep450fortargetedtreatmentofhepatocellularcarcinoma |