YK-4-279

A crystalline solid

In these schemes, ketone (4.0 equiv.) and a catalytic amount of diethylamine (10 drops) are added to a solution of substituted isatin (1.0 equiv.) in methanol (5 mL). The mixture is stirred at room temperature until starting material (substituted isatin) disappears completely. The resulting solution is concentrated and applied to flash chromatography eluting with hexane / ethyl acetate to afford pure product in quantitative yield. Further purification is done by recrystallization with hexane / ethyl acetate. An example compound synthesized by the above scheme includes: 4, 7-Dichloro-3- hydroxy-3-[2-(4-methoxyphenyl-2-oxoethyl)]-l, 3-dihydroindol-2-one: white solid; mp 149- 151 °C; 1H NMR (DMSO, 400 MH 1 z) delta 10.93 (s, 1H), 7.86 (d, 2H, J = 9.2 Hz), 7.26 (d, 1H, J = 8.8 Hz), 6.98 (d, 2H, J= 8.8 Hz), 6.86 (d, 1H, J = 8.4 Hz), 6.39 (s, 1H), 4.31 (d, 1H, J= 18.0 Hz), 3.80 (s, 3H), 3.61 (d, 1H, J= 18.0 Hz).Example 2' Synthesis of dehydrated 4, 7 dichloroisatm analogs [0144] A solution of 4, 7-dichloroisatin in 96percent H2S04 was stirred at room temperature to yield the reduced analogs. Example compounds: R2 = 4'-OCH3 (PT-1-33); 2', 4'- OCH3 (PT-1-39); 2', 3', 4', -OCH3 (PT-1-41); 4'-OC2H5 (PT-1-43); and 4'-N(CH3)2 (PT-1-38).General procedure: A solution of 4, 7-dichloroisatin in 96percent H2S04 was stirred at room temperature to yield the reduced analogs. Example compounds: R2 = 4 -OCH3 (PT-1-33); 2', 4'-OCH3 (PT-1-39); 2', 3', 4', -OCH3 (PT-1-41); 4'-OC2H5 (PT-1-43); and 4'-N(CH3)2 (PT-1-38).

An oncogenic fusion protein found in Ewing's sarcoma, a family of undifferentiated tumors which occur throughout the body. The binding of ES-FLI1 to RNA helicase A (RHA) promotes its oncogenic function. Inhibits protein-protein interactions between ES-FLI1 and RHA. At 10 μM, YK-4-279 blocks RHA binding to ES-FLI1 and induces apoptosis of a panel of Ewing's sarcoma tumor cell lines with IC50 values ranging from 0.5 to 2 μM.1 At 1.5 mg per dose, YK-4-279 reduces the growth of Ewing's sarcoma orthotopic xenografts in mice after treatment with the inhibitor for two weeks.