TitleDesign, synthesis, and biological evaluations of 2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoline analogs of combretastatin-A4.
Publication TypeJournal Article
Year of Publication2010
AuthorsLee, L, Robb, LM, Lee, M, Davis, R, Mackay, H, Chavda, S, Babu, B, O'Brien, EL, Risinger, AL, Mooberry, SL, Lee, M
JournalJ Med Chem
Volume53
Issue1
Pagination325-34
Date Published2010 Jan 14
ISSN1520-4804
KeywordsAnimals, Cell Cycle, Cell Line, Tumor, Cell Proliferation, Drug Design, Drug Screening Assays, Antitumor, HeLa Cells, Humans, Mice, Molecular Structure, Oxadiazoles, Stereoisomerism, Stilbenes, Structure-Activity Relationship
Abstract

<p>A total of 24 novel 2,5-diaryl-1,3,4-oxadiazoline analogs of combretastatin A-4 (CA-4, 1) were designed, synthesized, and evaluated for biological activities. The compounds represent two structural classes; the Type I class has three methoxy groups on the A ring and the Type II class has a single methoxy group on the A ring. Biological evaluations demonstrate that multiple structural features control the biological potency. Four of the compounds, 2-(3'-bromophenyl)-5-(3'',4'',5''-trimethoxyphenyl)-2-acetyl-2,3-dihydro-1,3,4-oxadiazoline (9l), 2-(2',5'-dimethoxyphenyl)-5-(3''-methoxyphenyl)-2-acetyl-2,3-dihydro-1,3,4-oxadiazoline (10h), 2-(3',4',5'-trimethoxyphenyl)-5-(3''-methoxyphenyl)-2-acetyl-2,3-dihydro-1,3,4-oxadiazoline (10i), and 2-(3',5'-dimethoxyphenyl)-5-(3''-methoxyphenyl)-2-acetyl-2,3-dihydro-1,3,4-oxadiazoline (10j), have potent antiproliferative activities against multiple cancer cell lines. Mechanistic studies indicate that they retain the microtubule disrupting effects of compound 1, including microtubule loss, the formation of aberrant mitotic spindles, and mitotic arrest. Compound 10i inhibits purified tubulin polymerization and circumvents drug resistance mediated by P-glycoprotein and betaIII tubulin expression. The oxadiazoline analog 10i is a promising lead candidate worthy of further investigation.</p>

DOI10.1021/jm901268n
Alternate JournalJ Med Chem
PubMed ID19894742
PubMed Central IDPMC2810428
Grant ListP30 CA054174 / CA / NCI NIH HHS / United States
P30 CA054174-079006 / CA / NCI NIH HHS / United States
R01 CA121138 / CA / NCI NIH HHS / United States
R01 CA121138-01A1 / CA / NCI NIH HHS / United States