title: 1-Piperazinylphthalazines as potential VEGFR-2 inhibitors and anticancer agents: Synthesis and in vitro biological evaluation.
abstract: In our endeavor towards the development of effective VEGFR-2 inhibitors, three novel series of phthalazine derivatives based on 1-piperazinyl-4-arylphthalazine scaffold were synthesized. All the newly prepared phthalazines 16a-k, 18a-e and 21a-g were evaluated in vitro for their inhibitory activity against VEGFR-2. In particular, compounds 16k and 21d potently inhibited VEGFR-2 at sub-micromolar IC50 values 0.35 ± 0.03 and 0.40 ± 0.04 μM, respectively. Moreover, seventeen selected compounds 16c-e, 16g, 16h, 16j, 16k, 18c-e and 21a-g were evaluated for their in vitro anticancer activity according to US-NCI protocol, where compounds 16k and 21d proved to be the most potent anticancer agents. While, compound 16k exhibited potent broad spectrum anticancer activity with full panel GI50 (MG-MID) value of 3.62 μM, compound 21d showed high selectivity toward leukemia and prostate cancer subpanels [subpanel GI50 (MG-MID) 3.51 and 5.15 μM, respectively]. Molecular docking of compounds16k and 21d into VEGFR-2 active site was performed to explore their potential binding mode.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
authors.forename: Sahar M
authors.initials: SM
authors.lastname: Abou-Seri
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, P.O. Box 11829, Egypt. Electronic address: wagdy2000@gmail.com.
authors.forename: Wagdy M
authors.initials: WM
authors.lastname: Eldehna
authors.affiliation: Biochemistry Department, Division of Genetic Engineering and Biotechnology, National Research Centre, Dokki, 12622, Giza, Egypt.
authors.forename: Mamdouh M
authors.initials: MM
authors.lastname: Ali
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Cairo, Abbassia, P.O. Box 11566, Egypt. Electronic address: dalal@pharma.asu.edu.eg.
authors.forename: Dalal A
authors.initials: DA
authors.lastname: Abou El Ella
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D062105:Molecular Docking Simulation; D010793:Phthalazines / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; C043388:phthalazine; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: 1-Piperazinylphthalazines; Anticancer activity; Synthesis; VEGFR-2 inhibitors