title: Synthesis, cytotoxic activity, and tubulin polymerization inhibitory activity of new pyrrol-2(3H)-ones and pyridazin-3(2H)-ones.
abstract: A series of new pyrrol-2(3H)-ones 4a-f and pyridazin-3(2H)-ones 7a-f were synthesized and characterized using different spectroscopic tools. Some of the tested compounds revealed moderate activity against 60 cell lines. The E form of the pyrrolones 4 showed good cytotoxic activity than both the Z form and the corresponding open amide form. Furthermore, the in vitro cytotoxic activity against HepG2 and MCF-7 cell lines revealed that compounds (E)4b, 6f and 7f showed good cytotoxic activity against HepG2 with IC50 values of 11.47, 7.11 and 14.80μM, respectively. Compounds (E)4b, 6f, 7d and 7f showed a pronounced inhibitory effect against cellular localization of tubulin. Flow cytometric analysis indicated that HepG2 cells treated with (E)4b showed a predominated growth arrest at the S-phase compared to that of G2/M-phase. Molecular modeling study using MOE® program indicated that most of the target compounds showed good binding of β-subunit of tubulin with the binding free energy (dG) values about -10kcal/mole.
authors.affiliation: Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
authors.forename: Samar Hafez
authors.initials: SH
authors.lastname: Abbas
authors.affiliation: Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt. Electronic address: gamal.aborahma@mu.edu.eg.
authors.forename: Gamal El-Din A A
authors.initials: Gel-D
authors.lastname: Abuo-Rahma
authors.affiliation: Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abdel-Aziz
authors.affiliation: Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt.
authors.forename: Omar M
authors.initials: OM
authors.lastname: Aly
authors.affiliation: Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia 61519, Egypt; Department of Pharmaceutical Chemistry, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
authors.forename: Eman A
authors.initials: EA
authors.lastname: Beshr
authors.affiliation: Cancer Biology Laboratory, Center of Excellence for Advanced Sciences, National Research Center, Dokki, Giza, Egypt.
authors.forename: Amira M
authors.initials: AM
authors.lastname: Gamal-Eldeen
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D058105:Polymerization / Q000187:drug effects; D011724:Pyridazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D011724:Pyridazines; D011758:Pyrroles; D014404:Tubulin
keywords: Cytotoxicity; Docking study; Immunofluorescence; Pyridazinone; Pyrrolone; Tubulin