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. 2010 Jan 14;53(1):325-34.
doi: 10.1021/jm901268n.

Design, synthesis, and biological evaluations of 2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoline analogs of combretastatin-A4

Lauren Lee  1 , Lyda M Robb, Megan Lee, Ryan Davis, Hilary Mackay, Sameer Chavda, Balaji Babu, Erin L O'Brien, April L Risinger, Susan L Mooberry, Moses Lee
Affiliations

Design, synthesis, and biological evaluations of 2,5-diaryl-2,3-dihydro-1,3,4-oxadiazoline analogs of combretastatin-A4

V体育官网 - Lauren Lee et al. J Med Chem. .

"VSports" Abstract

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 VSports手机版. .

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"VSports注册入口" Figures

Figure 1
Figure 1
Structures of combretastatin-A4 (CA-4, 1), its water-soluble derivate (CA-4P, 2), its amino analogs (3 and 4), combretastatin-A1 (CA-1, 5), combretastatin-A1 diphosphate (CA-1P, 6), along with the pyrazole (7) and pyrazoline (8) analogs. Two general types of oxadiazoline analogs were generated, including the Type I compounds 9a–l and the Type II compounds 10a–l.
Figure 2
Figure 2
Molecular ball and stick model of oxadiazoline 10i (A) and cis-4,3’,4’,5’-tetramethoxystilbene (B). Black represents carbon, blue nitrogen, gray hydrogen, and red oxygen.
Figure 3
Figure 3
Effects of 10i on cellular microtubules. A-10 cells were treated for 18 h with vehicle (A) or 1 µM 10i (B) and cellular microtubule structures visualized with indirect immunofluorescence techniques. Normal interphase microtubules are visible in panel A. The 10i-induced loss of interphase microtubules is shown in panel B.
Figure 4
Figure 4
In vitro tubulin polymerization assays. The polymerization of bovine brain tubulin was monitored turbidimetrically by absorbance at 340 nm at 37°C in the presence of a range of 10i concentrations.
Figure 5
Figure 5
Effects of 10i on mitotic spindles and cell cycle distribution. HeLa cells were treated with vehicle (A) or 0.50 µM 10i (B) for 18 h, fixed and cellular structures visualized by indirect immunofluorescence. Cellular microtubules were visualized with a β-tubulin antibody (green), centrosomes using a γ-tubulin antibody (red), and DNA using DAPI (blue). For the cell cycle distribution studies, MDA-MB-435 cells were treated for 18 h with vehicle (A) or 0.50 µM 10i then stained with Kirshan’s reagent and evaluation by flow cytometry.
Scheme 1
Scheme 1
Representation of hydrazone intermediate and oxadiazoline synthesis.
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References

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