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In silico QSAR of 1-benzoyl-3-benzylurea lead and its analogue compounds as anticancer
Published in Elida Zairina, Junaidi Khotib, Chrismawan Ardianto, Syed Azhar Syed Sulaiman, Charles D. Sands, Timothy E. Welty, Unity in Diversity and the Standardisation of Clinical Pharmacy Services, 2017
F. Suhud, C. Effendi, Siswandono
It is so due to the fact that approximately 60% of malignant tumors express a high concentration of VEGF. Such high percentage is a result of cellular responses stimulated by VEGF family by binding the tyrosine kinase receptors (the VEGFRs) on the cell surface. This stimulation causes VEGF family to dimerize and activate them through transphosphorylation. VEGFR and VEGFR-2 as the type II of the transmembrane TK receptor emerged on endothelial cells and on circulating bone marrow-derived endothelial progenitor cells. TK receptor plays the main role of VEGF-induced angiogenic signaling. In other words, VEGFR-2 is a novel targeted drug therapy. Previous biological and preclinical studies prove that the blocking of VEGFR-2 could be a promising strategy to inhibit tumor-induced angiogenesis (Fontanella C et al. 2014). One proven VEGFR-2 inhibitor on the market today is Sorafenibtosylate (Fig. 1).
Design, synthesis, apoptotic, and antiproliferative effects of 5-chloro-3- (2-methoxyvinyl)-indole-2-carboxamides and pyrido[3,4-b]indol-1-ones as potent EGFRWT/EGFRT790M inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Lamya H. Al-Wahaibi, Anber F. Mohammed, Fatema El-Zahraa S. Abdel Rahman, Mostafa H. Abdelrahman, Xuyuan Gu, Laurent Trembleau, Bahaa G. M. Youssif
Song et al. reported a series of indole derivatives as dual EGFR/VEGFR-2 inhibitors20. Compound III demonstrated dual inhibitory activities against EGFR and VEGFR-2, with IC50 values of 18 and 45 nM, respectively. Compound IV was also reported as a dual EGFR/VEGFR-2 inhibitor, with a prominent effect against EGFR compared to III, indicating the significance of morpholino moiety for EGFR inhibitory activity. Osimertinib (V) is an EGFR TKI with a selectivity index of about 200-fold towards EGFR T790M/L858R protein over wild-type EGFR21. Because of its selectivity and activity, osimertinib was approved by the FDA in 2015 to treat EGFR T790M-positive NSCLC21. We recently22 reported on the development of a novel series of 5-chloro-3-hydroxymethyl-indole-2-carboxamides VIa-l (Figure 1) as EGFR-TK antiproliferative agents. The most potent antiproliferative agent, compound VIc (R = 4-morpholin-4-yl), demonstrated significant EGFR inhibitory activity with an IC50 value of 0.12 µM.
Natural inspired piperine-based ureas and amides as novel antitumor agents towards breast cancer
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Diaaeldin M. Elimam, Abdullah A. Elgazar, Fardous F. El-Senduny, Ramadan A. El-Domany, Farid A Badria, Wagdy M. Eldehna
In the quest for finding new safe anticancer agents, two sets of thirty four piperine-based amides (5a–i) and ureas (8a–y) have been prepared, characterised successfully, and tested against three human cancer cell lines: TNBC (MDA-MB-231), ovarian (A2780CP) and hepatocellular (HepG2) following the protocol of MTT assay. Urea derivative 8q showed significant cytotoxic activity (IC50 = 18.7 µM) against MDA-MB-231cells better than piperine (IC50 = 47.8 µM) and 5-FU (IC50 = 38.5 µM). The flow cytometry study for TNBC MDA-MB-231cells showed that its treatment with 8q induced apoptosis at the late stage of cell division by causing cell arrest at G2-M phase and halted DNA synthesis by reducing S-phase population. Furthermore, enzyme inhibition assay showed that 8q is a promising VEGFR-2 inhibitor with IC50 = 251 nM, which reveals one of the potential mechanisms responsible for its anticancer activity. Also, the observed inhibitory activity was explained in the light of molecular docking which demonstrated that 8q was able to fulfil the requirement for binding properly in the active site of the enzyme by interacting with essential amino acid residues (Glu885, Cys919 and Asp1046) known to be necessary to achieve good VEGFR-2 inhibitory activity. Overall the gained results from this work sustained our strategy and granted us a robust opportunity for further optimisation of the natural piperine moiety to charge the therapeutic arsenal with efficient anticancer VEGFR-2 inhibitors.
Discovery of new nicotinamides as apoptotic VEGFR-2 inhibitors: virtual screening, synthesis, anti-proliferative, immunomodulatory, ADMET, toxicity, and molecular dynamic simulation studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Reda G. Yousef, Albaraa Ibrahim, Mohamed M. Khalifa, Wagdy M. Eldehna, Ibraheem M. M. Gobaara, Ahmed B. M. Mehany, Eslam B. Elkaeed, Aisha A. Alsfouk, Ahmed M. Metwaly, Ibrahim H. Eissa
Over the last few years, our research co-workers have developed a promising project concerning the discovery of new TK inhibitors, particularly with VEGFR-2 inhibitory activity13–20. In this regard, we have introduced several small molecules that were efficiently proved to possess strong VEGFR-2 inhibitory activities that were, in some cases, higher than that of the reference drugs. One of the most promising skeletons in our research project was the pyridine scaffold21. Pyridine was the backbone of several well-known VEGFR-2 inhibitors22–24. Taking sorafenib 1, the pyridine-based FDA-approved VEGFR-2 inhibitor, as a lead compound, different studies were developed to discover new inhibitors with higher potency and lower side effects, as well. Investigation of the binding of sorafenib to the VEGFR-2 active site gave us a brief about the main three pockets in which sorafenib interacts to perform its action25. However, the first pocket of the VEGFR-2 active site is an ATP pocket to which the pyridine moiety of sorafenib binds25. The second pocket is the DFG motif of the enzyme that interacts with the urea part of sorafenib via different H-bonding interactions26. While the last pocket is an allosteric lipophilic site where the terminal substituted phenyl ring of sorafenib occupies27 (Figure 1).