Browsing by Author "Arafa, Reem K."

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New proapoptotic chemotherapeutic agents based on the quinolone‑3‑carboxamide scafold acting byVEGFR‑2 inhibition
(Springer, 2023-06) El‑Fakharany, Zeinab S; Nissan, Yassin M; Sedky, Nada K; Arafa, Reem K.; Abou‑Seri, Sahar M.
In the current study, we designed and synthesized a series of new quinoline derivatives 10a-p as antiproliferative agents targeting cancer through inhibition of VEGFR-2. Preliminary molecular docking to assess the interactions of the designed derivatives with the binding site of VEGFR-2 (PDB code: 4ASD) displayed binding poses and interactions comparable to sorafenib. The synthesized compounds exhibited VEGFR-2 inhibitory activity with IC50 ranging from 36 nM to 2.23 μM compared to sorafenib (IC50 = 45 nM), where derivative 10i was the most potent. Additionally, the synthesized derivatives were evaluated in vitro for their cytotoxic activity against HepG2 cancer cell line. Seven compounds 10a, 10c, 10d, 10e, 10i, 10n and 10o (IC50 = 4.60, 4.14, 1.07, 0.88, 1.60, 2.88 and 2.76 μM respectively) displayed better antiproliferative activity than sorafenib (IC50 = 8.38 μM). Compound 10i was tested against Transformed Human Liver Epithelial-2 normal cell line (THLE-2) to evaluate its selective cytotoxicity. Furthermore, 10i, as a potent representative of the series, was assayed for its apoptotic activity and cell cycle kinetics’ infuence on HepG2, its efects on the gene expression of VEGFR-2, and protein expression of the apoptotic markers Caspase-7 and Bax. Compound 10i proved to have a potential role in apoptosis by causing signifcant increase in the early and late apoptotic quartiles, a remarkable activity in elevating the relative protein expression of Bax and Caspase-7 and a signifcant reduction of VEGFR-2 gene expression. Collectively, the obtained results indicate that compound 10i has a promising potential as a lead compound for the development of new anticancer agents
Novel sulfonamides bearing pyrrole and pyrrolopyrimidine moieties as carbonic anhydrase inhibitors: Synthesis, cytotoxic activity and molecular modeling
(Elsevier, 2014-11) Ghorab, Mostafa M.; Ceruso, Mariangela; Alsaid, Mansour S.; Nissan, Yassin M.; Arafa, Reem K.; Supuran, Claudiu T.
Novel sulfonamides bearing pyrrole and pyrrolopyrimidine moieties as carbonic anhydrase inhibitors: synthesis, cytotoxic activity and molecular modeling المؤلفون Mostafa M Ghorab, Mariangela Ceruso, Mansour S Alsaid, Yassin M Nissan, Reem K Arafa, Claudiu T Supuran تاريخ النشر 2014/11/24 مجلة European journal of medicinal chemistry المجلد 87 الصفحات 186-196 الناشر Elsevier Masson الوصف Novel pyrrole and pyrrolopyrimidine scaffold-based sulfonamides were designed and synthesized. The carbonic anhydrase (CA) inhibition ability of all derivatives was assessed against the human (h) cytosolic isoforms hCA I and II and the transmembrane, tumor-associated isoforms hCA IX and XII. Some of these sulfonamides were 6–8 fold more potent than the reference drug acetazolamide (AZA, Ki = 5.7 nM)) against hCA XII showing subnanomolar activity. The in vitro cytotoxicity of these derivatives was evaluated against MCF-7, where some derivatives were more cytotoxic than doxorubicin (IC50 = 8.02 μM) displaying IC50 values between 6.46 and 7.56 μM. Docking of these sulfonamides with CA XII was performed and their binding modes were comparable with that of AZA.
Selective VEGFR-2 inhibitors: Synthesis of pyridine derivatives, cytotoxicity and apoptosis induction profiling
(Elsevier Ltd, 2020-10) Abdel Haleem, Amal; Mansour, Amira O.; Abdel Kader, Marwa; Arafa, Reem K.
VEGFR-2 is a key regulator in cancer angiogenesis. This research displays the design and synthesis of novel 3-cyano-6-naphthylpyridine scaffold-based derivatives as selective VEGFR-2 inhibitors and cytotoxic agents. In vitro percent kinase activity inhibition screening against a panel of 23 kinases at a single high dose (30 nM) affirmed that VEGFR-2 was selectively the most responsive to inhibition by the investigated chemotypes. IC50 values determination demonstrated kinase inhibitory activities of the test compounds at the sub-nanomolar level. In vitro testing of the new compounds against two prostate cancer cell lines namely PC3 and DU145 and two breast cancer cell lines namely MCF-7 and MDA-MB435 confirmed their potent cytotoxic activity with IC50s at the nanomolar level. The most active compound against MCF-7 viz. 11d was subjected to an in vivo examination against a xenograft mouse model and was found effective. Studying the tissue mRNA expression levels of various cell cycle controlling biomolecules in 11d-treated MCF-7 cells demonstrated (i) upregulation of p53, p21 and p27, (ii) cleavage of PARP protein, (iii) activation of caspase-3, −8 and −9, (iv) downregulation of the anti-apoptotic protein Bcl, (v) upregulation of the pro-apoptotic protein Bax, and (vi) decreased expression of Cdks 2, 4, 6 and cyclin D1. Additionally, 11d affected a cell cycle arrest at the G1 phase in treated MCF-7 cells and an S phase arrest in MCF-7 p53 knockdown cells. Additionally, molecular docking was performed to predict how 11d might bind to its biological target VEGFR-2. Finally, in-silico ADME and drug-likeness profiling of these derivatives demonstrated favorable properties thereof.