title: Synthesis and biological activity of aminophthalazines and aminopyridazines as novel inhibitors of PGE2 production in cells.
abstract: This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE(2) in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE(2) reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R(1)=H, R(2)=p-CH(3)O) exhibited the most potent activity in cells (EC(50)=0.02 μM) and minimal inhibition of COX-2 activity (3% at 5 μM). Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models exhibiting good anti-cancer activity.
authors.affiliation: BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd., Oro Valley, AZ 85737, USA.
authors.forename: Federico
authors.initials: F
authors.lastname: Medda
authors.forename: Earlphia
authors.initials: E
authors.lastname: Sells
authors.forename: Hui-Hua
authors.initials: HH
authors.lastname: Chang
authors.forename: Justin
authors.initials: J
authors.lastname: Dietrich
authors.forename: Shashi
authors.initials: S
authors.lastname: Chappeta
authors.forename: Breland
authors.initials: B
authors.lastname: Smith
authors.forename: Vijay
authors.initials: V
authors.lastname: Gokhale
authors.forename: Emmanuelle J
authors.initials: EJ
authors.lastname: Meuillet
authors.forename: Christopher
authors.initials: C
authors.lastname: Hulme
mesh_terms: D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D014183:Transplantation, Heterologous
chemical_list: C012730:5-aminophthalazine; D000631:Aminopyridines; D000970:Antineoplastic Agents; D010793:Phthalazines; D015232:Dinoprostone