TY - JOUR
T1 - Design, synthesis, and biological evaluations of 2,5-diaryl-2,3-dihydro-1, 3,4-oxadiazoline analogs of combretastatin-A4
AU - Lee, Lauren
AU - Robb, Lyda M.
AU - Lee, Megan
AU - Davis, Ryan
AU - Mackay, Hilary
AU - Chavda, Sameer
AU - Babu, Balaji
AU - O'Brien, Erin L.
AU - Risinger, April L.
AU - Mooberry, Susan L.
AU - Lee, Moses
PY - 2010
Y1 - 2010
N2 - 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 (91), 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 βIII tubulin expression. The oxadiazoline analog 10i is a promising lead candidate worthy of further investigation.
AB - 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 (91), 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 βIII tubulin expression. The oxadiazoline analog 10i is a promising lead candidate worthy of further investigation.
UR - http://www.scopus.com/inward/record.url?scp=74849140125&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=74849140125&partnerID=8YFLogxK
U2 - 10.1021/jm901268n
DO - 10.1021/jm901268n
M3 - Article
C2 - 19894742
AN - SCOPUS:74849140125
SN - 0022-2623
VL - 53
SP - 325
EP - 334
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -