Journal of Medicinal Chemistry Article Figure 2. Eﬀect of PUB-SOs 4, 16, 17, 29−31, 33, 40, 41, 45−47, 49, and cDDP on the phosphorylation of histone H2AX into γH2AX. anilines 74−91 using iron powder in the presence of HCl or SnCl2·2H2O to obtain compound 59. PUB-SO and PUB-SA derivatives substituted with a CEU (4−23), a CPU (24−39), or a EU (40−55) moiety were prepared by nucleophilic addition of 2-chloroethyl isocyanate, 3-chloropropyl isocyanate, or ethyl isocyanate, respectively, to the corresponding anilines. The diﬀerent nucleophilicity or electrophilicity of the anilines and isocyanates used as starting materials led us to use various bases (4-dimethylaminopyridine and pyridine), solvents (THF, acetonitrile, and methylene chloride), and reaction conditions (temperature, microwave heating, etc.) to optimize reaction yields. Removal of the tert-butyldimethylsilyl protecting group on compounds 9, 14, 27, 32, 43, and 48 into their corresponding phenols was performed in the presence of tetra-n-butylammonium ﬂuoride (TBAF). Of note, the addition of the isocyanate to aniline provides low to moderate yields in the synthesis of PUB-SO and PUB- SA derivatives. The yields for the nucleophilic addition are even lower when PUB-SAs are involved or when the phenyl ring B is substituted at position 4 by a tert-butyldimethylsilyl group. Antiproliferative Activity. The antiproliferative activity of PUB-SOs and PUB-SAs was assessed in three human cancer 6197 dx.doi.org/10.1021/jm3006492 | J. Med. Chem. 2012, 55, 6194−6208