Novel pyrrolizines bearing 3,4,5-trimethoxyphenyl moiety: design, synthesis, molecular docking, and biological evaluation as potential multi-target cytotoxic agents
Creators: name: Shawky, Ahmed M.
name: Ibrahim, Nashwa A.
name: Abdalla, Ashraf N.
name: Abourehab, Mohammed A. S.
name: Gouda, Ahmed M.
Publisher: name: Taylor & Francis
Year: 2021
Subjects: subject: Biophysics
subject: Biochemistry
subject: Cell Biology
subject: Pharmacology
subject: 39999 Chemical Sciences not elsewhere classified
subject: FOS: Chemical sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: FOS: Biological sciences
subject: Cancer
subject: Hematology

description: 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 <b>16a–e</b> showed higher cytotoxicity than their corresponding Schiff bases <b>15a–e</b>. Compounds <b>16a</b>,<b>b</b>,<b>d</b> also inhibited the growth of MCF-7/ADR cells with IC<sub>50</sub> in the range of 0.52–6.26 μM. Interestingly, the new compounds were less cytotoxic against normal MRC-5 cells (IC<sub>50</sub>=0.155–17.08 μM). Mechanistic studies revealed the ability of compounds <b>16a</b>,<b>b</b>,<b>d</b> to inhibit tubulin polymerisation and multiple oncogenic kinases. Moreover, compounds <b>16a</b>,<b>b</b>,<b>d</b> induced preG<sub>1</sub> and G<sub>2</sub>/M cell cycle arrest and early apoptosis in MCF-7 cells. The molecular docking analyses of compounds <b>16a</b>,<b>b</b>,<b>d</b> 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 <b>16a</b>,<b>b</b>,<b>d</b> could serve as promising lead compounds for the future development of new potent anticancer agents.HighlightsTwo new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moieties were synthesized.Compounds <b>16a</b>,<b>b</b>,<b>d</b> displayed the highest cytotoxicity against the three cancer cell lines.Kinase profiling test revealed inhibition of multiple oncogenic kinases by compounds <b>16a</b>,<b>b</b>,<b>d</b>.Compounds <b>16a</b>,<b>b</b>,<b>d</b> exhibited weak to moderate inhibition of tubulin-polymerization.Compounds <b>16a</b>,<b>b</b>,<b>d</b> induced preG<sub>1</sub> and G<sub>2</sub>/M cell cycle arrest and early apoptosis in MCF-7 cells.Docking studies revealed high binding affinities for compounds <b>16a</b>,<b>b</b> towards tubulin and CDK-2. Two new series of pyrrolizines bearing 3,4,5-trimethoxyphenyl moieties were synthesized. Compounds <b>16a</b>,<b>b</b>,<b>d</b> displayed the highest cytotoxicity against the three cancer cell lines. Kinase profiling test revealed inhibition of multiple oncogenic kinases by compounds <b>16a</b>,<b>b</b>,<b>d</b>. Compounds <b>16a</b>,<b>b</b>,<b>d</b> exhibited weak to moderate inhibition of tubulin-polymerization. Compounds <b>16a</b>,<b>b</b>,<b>d</b> induced preG<sub>1</sub> and G<sub>2</sub>/M cell cycle arrest and early apoptosis in MCF-7 cells. Docking studies revealed high binding affinities for compounds <b>16a</b>,<b>b</b> towards tubulin and CDK-2.