title: Synthesis, structure-activity relationships, and antitumor studies of 2-benzoxazolyl hydrazones derived from alpha-(N)-acyl heteroaromatics.
abstract: Recently we have described the antitumor activities of 2-benzoxazolylhydrazones derived from 2-formyl and 2-acetylpyridines. In search of a more efficacious analogue, compounds in which the 2-acetylpyridine moiety has been replaced by 2-acylpyridine and alpha-(N)-acetyldiazine/quinoline groups have been synthesized. The 2-acylpyridyl hydrazones inhibited in vitro cell proliferation in the nM range, whereas the hydrazones derived from the alpha-(N)-acetyldiazines/quinolines inhibited cell growth in the muM range. Compounds tested in the NCI-60 cell assay were effective inhibitors of leukemia, colon, and ovarian cancer cells. E-13k [N-benzoxazol-2-yl-N'-(1-isoquinolin-3-yl-ethylidene)-hydrazine] inhibited the proliferation of MCF-7 breast carcinoma cells more efficiently than nontransformed MCF-10A cells. It is not transported by P-glycoprotein and a weak MRP substrate. Increased concentrations of serum or alpha(1)-acid glycoprotein did not reduce the antiproliferative activity of the compound. In the in vivo hollow fiber assay, E-13k achieved a score of 24, with a net cell kill of OVCAR-3 (ovarian) and SF2-95 (CNS) tumor cells.
authors.affiliation: Institute of Pharmacy, Department of Pharmaceutical Chemistry, University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria. johnny.easmon@uibk.ac.at
authors.forename: Johnny
authors.initials: J
authors.lastname: Easmon
authors.forename: Gerhard
authors.initials: G
authors.lastname: Pürstinger
authors.forename: Katrin-Sofia
authors.initials: KS
authors.lastname: Thies
authors.forename: Gottfried
authors.initials: G
authors.lastname: Heinisch
authors.forename: Johann
authors.initials: J
authors.lastname: Hofmann
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001583:Benzoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009928:Organ Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001583:Benzoxazoles; D006835:Hydrazones; C515137:N-benzoxazol-2-yl-N'-(1-isoquinolin-3-ylethylidene)hydrazine