Publications by authors named "Alaa Elwan"

3 Publications

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Discovery of new VEGFR-2 inhibitors based on bis([1, 2, 4]triazolo)[4,3-:3',4'-]quinoxaline derivatives as anticancer agents and apoptosis inducers.

J Enzyme Inhib Med Chem 2021 Dec;36(1):1093-1114

Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

Herein, a new wave of bis([1, 2, 4]triazolo)[4,3-:3',4'-]quinoxaline derivatives have been successfully designed and synthesised. The synthesised derivatives were biologically investigated for their cytotoxic activities against HepG2 and MCF-7. Also, the tested compounds were further examined for their VEGFR-2 inhibitory activity. The most promising derivative was further investigated for its apoptotic behaviour in HepG2 cell lines using flow cytometric and western-plot analyses. Additional studies were performed to predict how the synthesised compounds can bind to VEGFR-2 and to determine the drug-likeness profiling of these derivatives. The results revealed that compounds , , , , and displayed the highest antiproliferative activities against the two cell lines with IC values ranging from 6.4 to 19.4 µM. Furthermore, compounds , , , , , , , and showed the highest VEGFR-2 inhibitory activities with IC values ranging from 3.7 to 11.8 nM, comparing to sorafenib (IC = 3.12 nM). Moreover, compound arrested the HepG2 cell growth at the G2/M phase and induced apoptosis by 40.12% compared to the control cells (7.07%). As well, such compound showed a significant increase in the level of caspase-3 (1.36-fold), caspase-9 (2.80-fold), and BAX (1.65-fold), and exhibited a significant decrease in Bcl-2 level (2.63-fold).
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http://dx.doi.org/10.1080/14756366.2021.1915303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168755PMC
December 2021

Discovery of thieno[2,3-d]pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents.

Bioorg Chem 2021 Jul 27;112:104947. Epub 2021 Apr 27.

Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Ad Diriyah 13713, Riyadh, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt. Electronic address:

Vascular endothelial growth factor-2 (VEGFR-2) is considered one of the most important factors in tumor angiogenesis, and consequently a number of anticancer therapeutics have been developed to inhibit VEGFR-2 signaling. Accordingly, eighteen derivatives of thieno[2,3-d]pyrimidines having structural characteristics similar to VEGFR-2 inhibitors were designed and synthesized. Anticancer activities of the new derivatives were assessed against three human cancer cell lines (HCT-116, HepG2, and MCF-7) using MTT. Sorafenib was used as positive control. Compounds 17c-i, and 20b showed excellent anticancer activities against HCT-116 and HepG2 cell lines, while compounds 17i and 17g was found to be active against MCF-7 cell line. Compound 17f exhibited the highest cytotoxic activities against the examined cell lines, HCT-116 and HepG2, with IC values of 2.80 ± 0.16 and 4.10 ± 0.45 µM, respectively. Aiming at exploring the mechanism of action of these compounds, the most active cytotoxic derivatives were in vitro tested for their VEGFR-2 inhibitory activity. Compound 17f showed high activity against VEGFR-2 with an IC value of 0.23 ± 0.03 µM, that is equal to that of reference, sorafenib (IC = 0.23 ± 0.04 µM). Molecular docking studies also were performed to investigate the possible binding interactions of the target compounds with the active sites of VEGFR-2. The synthesized compounds were analyzed for their ADMET and toxicity properties. Results showed that most of the compounds have low to very low BBB penetration levels and they have non-inhibitory effect against CYP2D6. All compounds were predicted to be non-toxic against developmental toxicity potential model except compounds 17b and 20b.
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http://dx.doi.org/10.1016/j.bioorg.2021.104947DOI Listing
July 2021

Design, synthesis, molecular docking and anti-proliferative evaluations of [1,2,4]triazolo[4,3-a]quinoxaline derivatives as DNA intercalators and Topoisomerase II inhibitors.

Bioorg Chem 2020 12 21;105:104399. Epub 2020 Oct 21.

Pharmaceutical Medicinal Chemistry and Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Nasr City 11884, Cairo, Egypt. Electronic address:

In view of their DNA intercalation activities as anticancer agents, novel twenty four [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized and evaluated against HepG2, HCT-116 and MCF-7 as DNA intercalators and Top II enzyme inhibitors. The data obtained from molecular modeling studies revealed that, our small aromatic molecules were concluded to act through two ways firstly, through non-covalent interaction with the directly bound proteins to DNA hence inhibit topoisomerase-II enzyme. The second is through non-covalently binding to double helical structures of DNA either by intercalating binder as in compounds 10 and 11 or by minor groove binding as in compounds 8 and 8. Cytotoxic activity indicated that MCF-7 and HepG2 were the most sensitive cell lines to the influence of the new derivatives respectively. In particular, compounds 10, 11 and 8 were found to be the most potent derivatives overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC = (4.55 ± 0.3, 6.18 ± 0.8 and 3.93 ± 0.6 µM), (5.61 ± 0.5, 6.49 ± 0.5and 3.71 ± 0.3 µM) and (4.66 ± 0.3, 8.08 ± 0.8 and 5.11 ± 0.7 µM) respectively. The three derivatives exhibited higher activities than doxorubicin, (IC = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 µM respectively), against HepG2 and MCF-7 but 8 exhibited nearly the same activity against HCT116 cancer cell lines respectively. The most active derivatives 8, 10,, 11, 13 and 14 were evaluated for their DNA binding activities. The tested compounds displayed very good to moderate DNA-binding affinities. Compounds 10 11, 8, 8, 8 and 8 displayed the highest binding affinities. These compounds potently intercalate DNA at decreased IC values of 25.27 ± 1.2, 27.47 ± 2.1, 27.54 ± 3.2, 27.78 ± 1.3, 29.15 ± 1.8 and 30.23 ± 3.7 µM respectively, which were less than that of doxorubicin (31.27 ± 1.8). Furthermore, the most active cytotoxic compounds 8, 8, 8, 8, 10 and 11 were selected to evaluate their inhibitory activities against Topo II enzyme. All the tested compounds could interfere with the Topo II activity. They exhibited very good inhibitory activities with IC values ranging from 0.379 ± 0.07 to 0.813 ± 0.14 µM that were lower than that of doxorubicin (IC = 0.94 ± 0.4 µM). For a great extent, the reported results were in agreement with that of in vitro cytotoxicity activity, DNA binding and molecular modeling studies.
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http://dx.doi.org/10.1016/j.bioorg.2020.104399DOI Listing
December 2020