title: Design, synthesis and in vitro antitumor activity of novel N-substituted-4-phenyl/benzylphthalazin-1-ones.
abstract: A novel series of N-substituted-4-phenylphthalazin-1-ones 14a-g bearing different anilines at the N-2 of phthalazin-1-one scaffold via acetyl-flexible linker was designed and synthesized for the development of potential anticancer agents. Compounds 19a-g were synthesized by insertion of methylene (CH2) bridge at C4-position of 14a-g to provide a flexibility for the phenyl group. The newly synthesized compounds 14a-g and 19a-g were evaluated for their anti-proliferative activity against three human tumor cell lines HepG2 hepatocellular carcinoma, HT-29 colon cancer and MCF-7 breast cancer. In particular, HepG2 and HT-29 cancer cell lines were more susceptible to the synthesized derivatives. Compound 19d (IC50 = 1.2 ± 0.09 μM) was found to be the most potent derivative against HepG2 as it was 2.9 times more active than doxorubicin (IC50 = 3.45 ± 0.54) and sorafenib (IC50 = 3.5 ± 1.04 μM). Compounds 14e, 14g, 19d and 19g with IC50 = (3.29 ± 0.45), (3.50 ± 0.846), (1.20 ± 0.09) and (3.52 ± 0.70) μM, respectively, were found to be active candidates against HepG2 cancer cells. Compounds 14e, 14g, 19d and 19g were able to induce apoptosis in HepG2, this was assured by; the significant increase in the percentage of annexin V-FITC-positive apoptotic cells (UR + LR), the down-regulation of the anti-apoptotic protein Bcl-2 and the up-regulation of the pro-apoptotic protein Bax, in addition to boosting caspase-3 levels. Moreover, cytotoxicity evaluation of the newly synthesized compounds in HT-29 revealed that compounds 14e, 14f, 19e and 19f (IC50 = 3.05 ± 0.78, 4.02 ± 1.18, 3.68 ± 0.79 and 2.98 ± 0.47 μM, respectively) were more potent than doxorubicin (IC50 = 7.70 ± 1.78 μM).
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, Egyptian Russian University, P.O. Box 11829, Badr City, Cairo, Egypt. Electronic address: wagdy2000@gmail.com.
authors.forename: Wagdy M
authors.initials: WM
authors.lastname: Eldehna
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, Egyptian Russian University, P.O. Box 11829, Badr City, Cairo, Egypt.
authors.forename: Hany S
authors.initials: HS
authors.lastname: Ibrahim
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia; Department of Applied Organic Chemistry, National Research Center, P.O. Box 12622, Dokki, Giza, Egypt. Electronic address: hatem_741@yahoo.com.
authors.forename: Hatem A
authors.initials: HA
authors.lastname: Abdel-Aziz
authors.affiliation: Department of Biology, School of Sciences and Engineering (SSE), The American University in Cairo, P.O. Box 11835, New Cairo, Egypt.
authors.forename: Noha N
authors.initials: NN
authors.lastname: Farrag
authors.affiliation: Department of Biology, School of Sciences and Engineering (SSE), The American University in Cairo, P.O. Box 11835, New Cairo, Egypt; Department of Pharmacology and Toxicology, College of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt.
authors.forename: Mohieldin M
authors.initials: MM
authors.lastname: Youssef
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D010793:Phthalazines
keywords: Antitumor activity; Apoptosis; HepG2; Phthalazin-1-one