title: Design, synthesis and structure-activity relationship of novel semi-synthetic flavonoids as antiproliferative agents.
abstract: Various flavonoid scaffold based derivatives viz furochalcones (3a-e, 6a-d and 9a-d), furoflavones (10a-d, 11a-d, 12a-d, 18a&b), flavones (21a-d), furoaurones (13a,b, 14a-d and 15a-d) and 7-styrylfurochromones (22a-d and 25a-e) were designed and synthesized. The novel compounds were evaluated for their antiproliferative activity against a panel of 60 cancer cell lines comprising 9 types of tumors. Ten compounds belonging to the major subgroups of flavonoids viz furochalcones (3a, 3d, 6b, 9a and 9b), furoflavones (12a and 12c), furoaurones (15d), styrylfurochromones (25b and 25e) showed very promising activity. These active compounds were also evaluated in vitro as kinase inhibitors against CDK2/cyclin E1, CDK4/cyclin D1 and GSK-3β and the best inhibition was displayed against GSK-3β with the allylfurochalcone derivative 9b exhibiting 80% decrease in GSK-3β catalytic activity. On the other hand, the styrylfurochromone 25e interestingly showed a 13% enhancement of GSK-3β catalytic power and a 12% reduction in CDK4/cyclin D1 activity. Finally, the in vivo anti-tumor activity of 25e was evaluated against breast cancer induced in mice. The results showed a profound anti-tumor effect of 25e that accompanies a significant increase and decrease in the levels of GSK-3β and cyclin D1, respectively.
authors.affiliation: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt.
authors.forename: F A
authors.initials: FA
authors.lastname: Ragab
authors.affiliation: Medicinal Chemistry Department, Faculty of Pharmacy, Sana'a University, Sana'a, Yemen.
authors.forename: T A A
authors.initials: TA
authors.lastname: Yahya
authors.affiliation: Pharmacology and Toxicology Department, Faculty of Pharmacy, October University for Modern Sciences and Arts, Egypt.
authors.forename: M M
authors.initials: MM
authors.lastname: El-Naa
authors.affiliation: Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, 11562 Cairo, Egypt. Electronic address: rkarafa@cu.edu.eg.
authors.forename: R K
authors.initials: RK
authors.lastname: Arafa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005419:Flavonoids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids
keywords: Cytotoxicity; Furoaurones; Furochalcones; Furoflavones; Furostyrylfurochromones; Kinase inhibition