Kemnitzer William, Jiang Songchun, Wang Yan, Kasibhatla Shailaja, Crogan-Grundy Candace, Bubenik Monica, Labrecque Denis, Denis Real, Lamothe Serge, Attardo Giorgio, Gourdeau Henriette, Tseng Ben, Drewe John, Cai Sui Xiong
EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
Bioorg Med Chem Lett. 2008 Jan 15;18(2):603-7. doi: 10.1016/j.bmcl.2007.11.078. Epub 2007 Nov 28.
As a continuation of our efforts to discover and develop apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored modifications at the 2- and 3-positions. It was found that replacement of the 3-cyano group by an ester, including methyl and ethyl ester, resulted in >200-fold reduction of activity. Conversion of the 2-amino group into an amide or urea resulted in 4- to 10-fold drop of activity. Similarly, converting the 2-amino group into a hydrogen resulted in 4- to 10-fold reduction of activity. Compound 3d was highly active with an EC(50) value of 29 nM and a GI(50) value of 6 nM in T47D cells. Importantly, the 2-H analog 3d was found to be much more stable under acidic conditions compared to the 2-NH(2) analog 3b, suggesting that 2-H analogs might have better bioavailability than the 2-NH(2) analogs.
作为我们发现和开发凋亡诱导剂4-芳基-4H-色烯作为新型抗癌药物工作的延续，我们探索了2位和3位的修饰。结果发现，用酯（包括甲酯和乙酯）取代3-氰基会导致活性降低200倍以上。将2-氨基转化为酰胺或脲会导致活性下降4至10倍。同样，将2-氨基转化为氢会导致活性降低4至10倍。化合物3d在T47D细胞中具有高活性，EC(50)值为29 nM，GI(50)值为6 nM。重要的是，发现2-H类似物3d在酸性条件下比2-NH(2)类似物3b稳定得多，这表明2-H类似物可能比2-NH(2)类似物具有更好的生物利用度。
