Design, synthesis, and biological evaluations of 2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoline analogs of combretastatin-A4.
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.
Lee
Lauren
L
Department of Chemistry and the Division of Natural and Applied Sciences, Hope College, Michigan 49423, USA. lee@hope.edu
Robb
Lyda M
LM
Lee
Megan
M
Davis
Ryan
R
Mackay
Hilary
H
Chavda
Sameer
S
Babu
Balaji
B
O'Brien
Erin L
EL
Risinger
April L
AL
Mooberry
Susan L
SL
Lee
Moses
M
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D010069:Oxadiazoles / Q000737:chemistry*; D013237:Stereoisomerism; D013267:Stilbenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D010069:Oxadiazoles; D013267:Stilbenes; C058728:fosbretabulin