Antiproliferative and Antiangiogenic Properties of New VEGFR-2-targeting 2-thioxobenzo[<i>g</i>]quinazoline Derivatives (In Vitro)
A series of 3-ethyl(methyl)-2-thioxo-2,3-dihydrobenzo[<i>g</i>]quinazolines (<b>1</b>–<b>17</b>) were synthesized, characterized, and evaluated in vitro for their antiangiogenesis VEGFR-2-targeting, antiproliferative, and antiapoptotic activities against breast MC...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-12-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/25/24/5944 |
| _version_ | 1797544593445617664 |
|---|---|
| author | Hatem A. Abuelizz Mohamed Marzouk Ahmed H. Bakheit Hanem M. Awad Maha M. Soltan Ahmed M. Naglah Rashad Al-Salahi |
| author_facet | Hatem A. Abuelizz Mohamed Marzouk Ahmed H. Bakheit Hanem M. Awad Maha M. Soltan Ahmed M. Naglah Rashad Al-Salahi |
| author_sort | Hatem A. Abuelizz |
| collection | DOAJ |
| description | A series of 3-ethyl(methyl)-2-thioxo-2,3-dihydrobenzo[<i>g</i>]quinazolines (<b>1</b>–<b>17</b>) were synthesized, characterized, and evaluated in vitro for their antiangiogenesis VEGFR-2-targeting, antiproliferative, and antiapoptotic activities against breast MCF-7 and liver HepG2 cells. Flow cytometry was used to determine cancer-cell cycle distributions, and apoptosis was detected using annexin-V-FITC (V) and propidium iodide (PI) dyes. Fluorescence microscopy, in combination with Hoechst staining was used to detect DNA fragmentation. Most of the tested benzo[<i>g</i>]quinazolines demonstrated promising activity (IC<sub>50</sub> = 8.8 ± 0.5–10.9 ± 0.9 μM) and (IC<sub>50</sub> = 26.0 ± 2.5–40.4 ± 4.1 μM) against MCF-7 and HepG2, respectively. Doxorubicin was used as a reference drug. Compounds <b>13</b>–<b>15</b> showed the highest activity against both cancer cell lines. Differential effects were detected by cell-cycle analysis, indicating similarities in the actions of <b>13</b> and <b>14</b> against both MCF7 and HepG2, involving the targeting of G1 and S phases, respectively. Compound <b>15</b> showed similar indices against both cells, indicating that its cytotoxicity toward the examined cancer cells could be unselective. Interestingly, <b>14</b> and <b>15</b> showed the highest apoptosis (30.76% and 25.30%, respectively) against MCF-7. The DNA fragmentation results agreed well with the apoptosis detected by flow cytometry. In terms of antiangiogenesis activity, as derived from VEGFR-2 inhibition, <b>13</b> and <b>15</b> were comparable to sorafenib and effected 1.5- and 1.4-fold inhibition relative to the standard sorafenib. A docking study was conducted to investigate the interaction between the synthesized benzo[<i>g</i>]quinazolines and the ATP-binding site within the catalytic domain of VEGFR-2. |
| first_indexed | 2024-03-10T14:02:43Z |
| format | Article |
| id | doaj.art-2393c0a303f8407bb7f88057c4c19e9b |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T14:02:43Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-2393c0a303f8407bb7f88057c4c19e9b2023-11-21T00:56:04ZengMDPI AGMolecules1420-30492020-12-012524594410.3390/molecules25245944Antiproliferative and Antiangiogenic Properties of New VEGFR-2-targeting 2-thioxobenzo[<i>g</i>]quinazoline Derivatives (In Vitro)Hatem A. Abuelizz0Mohamed Marzouk1Ahmed H. Bakheit2Hanem M. Awad3Maha M. Soltan4Ahmed M. Naglah5Rashad Al-Salahi6Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaDepartment of Tanning Materials and Leather Technology, National Research Centre, 33 El-Bohouth St. (Former El-Tahrir St.), Dokki, Cairo 12622, EgyptDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaDepartment of Tanning Materials and Leather Technology, National Research Centre, 33 El-Bohouth St. (Former El-Tahrir St.), Dokki, Cairo 12622, EgyptBiology Unit, Central Laboratory for Pharmaceutical and Drug Industries Research Division, Chemistry of Medicinal Plants Department, National Research Centre, El Bohouth St. 33, Dokki, Cairo 12622, EgyptDepartment of Pharmaceutical Chemistry, Drug Exploration and Development Chair (DEDC), College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaA series of 3-ethyl(methyl)-2-thioxo-2,3-dihydrobenzo[<i>g</i>]quinazolines (<b>1</b>–<b>17</b>) were synthesized, characterized, and evaluated in vitro for their antiangiogenesis VEGFR-2-targeting, antiproliferative, and antiapoptotic activities against breast MCF-7 and liver HepG2 cells. Flow cytometry was used to determine cancer-cell cycle distributions, and apoptosis was detected using annexin-V-FITC (V) and propidium iodide (PI) dyes. Fluorescence microscopy, in combination with Hoechst staining was used to detect DNA fragmentation. Most of the tested benzo[<i>g</i>]quinazolines demonstrated promising activity (IC<sub>50</sub> = 8.8 ± 0.5–10.9 ± 0.9 μM) and (IC<sub>50</sub> = 26.0 ± 2.5–40.4 ± 4.1 μM) against MCF-7 and HepG2, respectively. Doxorubicin was used as a reference drug. Compounds <b>13</b>–<b>15</b> showed the highest activity against both cancer cell lines. Differential effects were detected by cell-cycle analysis, indicating similarities in the actions of <b>13</b> and <b>14</b> against both MCF7 and HepG2, involving the targeting of G1 and S phases, respectively. Compound <b>15</b> showed similar indices against both cells, indicating that its cytotoxicity toward the examined cancer cells could be unselective. Interestingly, <b>14</b> and <b>15</b> showed the highest apoptosis (30.76% and 25.30%, respectively) against MCF-7. The DNA fragmentation results agreed well with the apoptosis detected by flow cytometry. In terms of antiangiogenesis activity, as derived from VEGFR-2 inhibition, <b>13</b> and <b>15</b> were comparable to sorafenib and effected 1.5- and 1.4-fold inhibition relative to the standard sorafenib. A docking study was conducted to investigate the interaction between the synthesized benzo[<i>g</i>]quinazolines and the ATP-binding site within the catalytic domain of VEGFR-2.https://www.mdpi.com/1420-3049/25/24/5944benzoquinazolinesMCF-7HepG2MTT assayapoptosisVEGFR-2 |
| spellingShingle | Hatem A. Abuelizz Mohamed Marzouk Ahmed H. Bakheit Hanem M. Awad Maha M. Soltan Ahmed M. Naglah Rashad Al-Salahi Antiproliferative and Antiangiogenic Properties of New VEGFR-2-targeting 2-thioxobenzo[<i>g</i>]quinazoline Derivatives (In Vitro) Molecules benzoquinazolines MCF-7 HepG2 MTT assay apoptosis VEGFR-2 |
| title | Antiproliferative and Antiangiogenic Properties of New VEGFR-2-targeting 2-thioxobenzo[<i>g</i>]quinazoline Derivatives (In Vitro) |
| title_full | Antiproliferative and Antiangiogenic Properties of New VEGFR-2-targeting 2-thioxobenzo[<i>g</i>]quinazoline Derivatives (In Vitro) |
| title_fullStr | Antiproliferative and Antiangiogenic Properties of New VEGFR-2-targeting 2-thioxobenzo[<i>g</i>]quinazoline Derivatives (In Vitro) |
| title_full_unstemmed | Antiproliferative and Antiangiogenic Properties of New VEGFR-2-targeting 2-thioxobenzo[<i>g</i>]quinazoline Derivatives (In Vitro) |
| title_short | Antiproliferative and Antiangiogenic Properties of New VEGFR-2-targeting 2-thioxobenzo[<i>g</i>]quinazoline Derivatives (In Vitro) |
| title_sort | antiproliferative and antiangiogenic properties of new vegfr 2 targeting 2 thioxobenzo i g i quinazoline derivatives in vitro |
| topic | benzoquinazolines MCF-7 HepG2 MTT assay apoptosis VEGFR-2 |
| url | https://www.mdpi.com/1420-3049/25/24/5944 |
| work_keys_str_mv | AT hatemaabuelizz antiproliferativeandantiangiogenicpropertiesofnewvegfr2targeting2thioxobenzoigiquinazolinederivativesinvitro AT mohamedmarzouk antiproliferativeandantiangiogenicpropertiesofnewvegfr2targeting2thioxobenzoigiquinazolinederivativesinvitro AT ahmedhbakheit antiproliferativeandantiangiogenicpropertiesofnewvegfr2targeting2thioxobenzoigiquinazolinederivativesinvitro AT hanemmawad antiproliferativeandantiangiogenicpropertiesofnewvegfr2targeting2thioxobenzoigiquinazolinederivativesinvitro AT mahamsoltan antiproliferativeandantiangiogenicpropertiesofnewvegfr2targeting2thioxobenzoigiquinazolinederivativesinvitro AT ahmedmnaglah antiproliferativeandantiangiogenicpropertiesofnewvegfr2targeting2thioxobenzoigiquinazolinederivativesinvitro AT rashadalsalahi antiproliferativeandantiangiogenicpropertiesofnewvegfr2targeting2thioxobenzoigiquinazolinederivativesinvitro |