Synthesis, Structure−Activity Relationships, and Antitumor Studies of 2-Benzoxazolyl Hydrazones Derived from Alpha-(N)-acyl Heteroaromatics

• Published in: Journal of medicinal chemistry Vol. 49; no. 21; pp. 6343 - 6350
• Main Authors: Easmon, Johnny, Pürstinger, Gerhard, Thies, Katrin-Sofia, Heinisch, Gottfried, Hofmann, Johann
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 19-10-2006
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzoxazoles - chemical synthesis; Benzoxazoles - chemistry; Benzoxazoles - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; General aspects; Humans; Hydrazones - chemical synthesis; Hydrazones - chemistry; Hydrazones - pharmacology; Medical sciences; Organ Specificity; Pharmacology. Drug treatments; Stereoisomerism; Structure-Activity Relationship; Antineoplastic agent; Human; Benzoxazole derivatives; Isoquinoline derivatives; In vitro; In vivo; Cell line; Structure activity relation; Colon; Mammary gland; Hydrazone; Chemical synthesis; Tumor cell
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm060232u

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 In search of a more efficacious analogue, compounds in which the 2-acetylpyridine moiety has been replaced by 2-acylpyridine and α-(N)-acetyldiazine/quinoline groups have been synthesized.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 α-(N)-acetyldiazines/quinolines inhibited cell growth in the μM 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 α1-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.