eCF506

A library of 24 closely related analogs was developed by introducing small changes on key functional groups of eCF506 and their activity tested in MDA-MB-231 cells. IC50 values were subsequently determined against SRC and ABL for those compounds exhibiting high antiproliferative activity and for selected compounds with low activity. Analysis of the properties of compounds 12a–e demonstrated that the presence of a tertiary amino group at the position 4 of the pyperidinyl ring is essential for the activity. Substitution of the methyl groups by larger aliphatic rings was tolerated, with compounds 12d and 12e being among the most potent SRC inhibitors of the series. Removal of the pyrimidine ring (compound 12f) resulted in >3000-fold decrease in antiproliferative activity. Screening of compounds 12g–x evidenced the limited structural variations permitted at the top of the molecule to achieve high bioactivity. Most modifications of the Boc and the methoxy groups of the phenyl moiety at the C3 position led to a significant reduction in bioactivity. Even minor chemical modifications such as the substitution of the carbamate group by urea (12i) or amide (12j), or the change of the methoxy by OH (12s), resulted in >200-fold decrease in both antiproliferative properties and SRC inhibitory activity. Remarkably, introduction of a benzylamino group instead of the Boc was tolerated well, as observed from the bioactivity exhibited by compound 12m. However, introduction of endocyclic nitrogen atoms in the ring (see 12n and 12o) dramatically reduced compounds’ activity, particularly in the ortho position. Interestingly, while the methoxy group is required for maintaining high levels of activity when the Boc group is present in the structure (see 12s–u), substitution of the Boc group by an ester tolerated the elimination of the methoxy group (see 12w and 12x).