Title | Design, synthesis, and biological evaluations of 2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoline analogs of combretastatin-A4. |
Publication Type | Journal Article |
Year of Publication | 2010 |
Authors | Lee, L, Robb, LM, Lee, M, Davis, R, Mackay, H, Chavda, S, Babu, B, O'Brien, EL, Risinger, AL, Mooberry, SL, Lee, M |
Journal | J Med Chem |
Volume | 53 |
Issue | 1 |
Pagination | 325-34 |
Date Published | 2010 Jan 14 |
ISSN | 1520-4804 |
Keywords | Animals, 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> |
DOI | 10.1021/jm901268n |
Alternate Journal | J Med Chem |
PubMed ID | 19894742 |
PubMed Central ID | PMC2810428 |
Grant List | P30 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 |