Design, synthesis, and biological evaluation of new series of pyrrol-2(3H)-one and pyridazin-3(2H)-one derivatives as tubulin polymerization inhibitors

Abdelbaset, Mahmoud S.; Abdelrahman, Mostafa H.; Bukhari, Syed Nasir Abbas; Gouda, Ahmed M.; Youssif, Bahaa G.M.; Abdel‐Aziz, Mohamed; Abuo‐Rahma, Gamal El‐Din A.

doi:10.1016/j.bioorg.2020.104522

Cited by 8 publications

(10 citation statements)

References 44 publications

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“…The crystal structure of tubulin protein (pdb code: 5LYJ) co-crystallised with CA-4 28 was obtained from the Protein Data Bank ( https://www.rcsb.org/structure/5lyj ). The protein and ligand files were prepared following the previous report 29 , 41 .…”

Section: Resultsmentioning

confidence: 99%

“…The crystal structure of CDK2 bound to CAN508 (pdb code: 3TNW) 25 , EGFR bound to erlotinib (pdb code: 1M17) 26 , Aurora A bound to VX6 (pdb code: 3E5A) 27 , and tubulin bound to C-A4 28 , were obtained from protein data bank ( http://www.rcsb.org/pdb ). Ligand and protein files were prepared according to the previous report 13 , 29 . Docking and grid parameter files were prepared according to the previous reports 30 , 31 .…”

Section: Methodsmentioning

confidence: 99%

“…AutoDock (v.4.2) was used to perform the docking study 24 . The study was performed following the previous reports [29][30][31] . Validation of the docking procedures into the selected kinases was also performed according to our previous report 13 .…”

Section: Docking Study Into Protein Kinasesmentioning

confidence: 99%

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Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents

Shawky

Ibrahim

Abdalla

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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In the present study, two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety were designed, synthesised, and evaluated for their cytotoxic activity. The benzamide derivatives 16a-e showed higher cytotoxicity than their corresponding Schiff bases 15a-e. Compounds 16a,b,d also inhibited the growth of MCF-7/ADR cells with IC 50 in the range of 0.52-6.26 lM. Interestingly, the new compounds were less cytotoxic against normal MRC-5 cells (IC 50 ¼0.155-17.08 lM). Mechanistic studies revealed the ability of compounds 16a,b,d to inhibit tubulin polymerisation and multiple oncogenic kinases. Moreover, compounds 16a,b,d induced preG 1 and G 2 /M cell cycle arrest and early apoptosis in MCF-7 cells. The molecular docking analyses of compounds 16a,b,d into the active site in tubulin, CDK-2, and EGFR proteins revealed higher binding affinities compared to the co-crystallised ligands. These preliminary results suggested that compounds 16a,b,d could serve as promising lead compounds for the future development of new potent anticancer agents. HIGHLIGHTS 1. Two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moieties were synthesized. 2. Compounds 16a,b,d displayed the highest cytotoxicity against the three cancer cell lines. 3. Kinase profiling test revealed inhibition of multiple oncogenic kinases by compounds 16a,b,d. 4. Compounds 16a,b,d exhibited weak to moderate inhibition of tubulin-polymerization. 5. Compounds 16a,b,d induced preG 1 and G 2 /M cell cycle arrest and early apoptosis in MCF-7 cells. 6. Docking studies revealed high binding affinities for compounds 16a,b towards tubulin and CDK-2.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents

Shawky

Ibrahim

Abdalla

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…To examine whether a microtubule-targeting mechanism is behind the observed antiproliferative activity of the above hybrids, the effect of hybrids 9g-i and 10f-h on tubulin polymerization using two positive controls, a tubulin polymerization stabilizer (docetaxel) and a tubulin polymerization inhibitor (vincristine). [41,42] We could conclude from the results in Table 2, that hybrids 9g-i and 10f-h exhibited a very weak effect on the assembly of tubulin, proposing the presence of another mechanism for the detected antiproliferative activity besides EGFR inhibition.…”

Section: Tubulin Polymerization Inhibitory Activitymentioning

confidence: 99%

New 1,3,4‐oxadiazole‐chalcone/benzimidazole hybrids as potent antiproliferative agents

Hagar

Abbas

Abdelhamid

et al. 2022

Archiv der Pharmazie

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A series of new 1,3,4-oxadiazole-chalcone/benzimidazole hybrids 9a-o and 10a-k were designed and synthesized as potential antiproliferative agents. Hybrids 9a-o exhibited remarkable antiproliferative activities on different NCI-60 cell lines in a single-dose assay. The antiproliferative activities of the newly synthesized compounds were evaluated against a panel of four human cancer cell lines (A-549, MCF-7, Panc-1, and HT-29). Compounds 9g-i and their oxygen isosteres, 10f-h, exhibited promising antiproliferative activities with IC 50 values ranging from 0.80 to 2.27 µM compared to doxorubicin (IC 50 ranging from 0.90 to 1.41 µM).Furthermore, the inhibitory potency of these compounds against the epidermal growth factor receptor (EGFR) and BRAF V600E kinases was evaluated using erlotinib as a reference drug. Molecular modeling studies were done to investigate the binding mode of the most active hybrids in the ATP binding site of EGFR.

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“…Reports have shown the excellent biological activities of pyrrol-2-one and furan-2-ones including anti-cancer, antitumor, anti-HIV, antifungal, antibacterial, and anti-inflammatory. [56,57] Khan et al [58] explored the synthesis of various furan-2-one 23 and pyrrol-2-one derivatives 24 via multi-component reaction between differently substituted aldehydes, amides and dialkyl acetylenedicarboxylates (Scheme 22), with lemon juice as a green catalyst at 110 °C. Further, by employing seedless barberry (Berberis integerrima), Hazeri et al reported the synthesis of furan-2(5)-ones using the same reaction conditions.…”

Section: Synthesis Of Furan-2-one and Pyrrol-2-onementioning

confidence: 99%

Lemon Juice: A Versatile Biocatalyst and Green Solvent in Organic Transformations

et al. 2022

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Green chemistry is the basis for fast‐growing, eco‐friendly, alternative sustainable technologies for the development of chemical products without the use or generation of hazardous catalysts. The role of naturally occurring fruit juice as a catalyst or solvent in organic synthesis has gained focused interest across the globe. Lemon juice‐mediated synthesis has been widely explored recently as a highly significant, selective solvent and biocatalyst in organic synthesis. This review presents recent developments on lemon‐juice mediated transformations and their application to synthesize molecules or building blocks of pharmaceutical interest. We believe this review article will be of interest to researchers both in academic and industrial settings focused on developing novel pharmacophores from a green chemistry principles perspective.

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Design, synthesis, and biological evaluation of new series of pyrrol-2(3H)-one and pyridazin-3(2H)-one derivatives as tubulin polymerization inhibitors

Cited by 8 publications

References 44 publications

Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents

Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents

New 1,3,4‐oxadiazole‐chalcone/benzimidazole hybrids as potent antiproliferative agents

Lemon Juice: A Versatile Biocatalyst and Green Solvent in Organic Transformations

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