Atropisomeric trihalobenzocycloheptapyridine analogues provide stereoselective FPT inhibitors with antitumor activity Original Research Article

Introduction of bromine at the 10-position of 3-bromo-8-chloro-benzocycloheptapyridine analogues of type 3 results in formation of atropisomeric compounds of type (±)-1 and (±)-2 that are easily separable at room temperature on a ChiralPak® AD column providing pure atropisomers, (+)-1, (−)-1, and (+)-2 (−)-2, respectively. Evaluation of the FPT activity of these atropisomers revealed that compounds (+)-1 and (+)-2 were more potent in the FPT enzyme and cellular assay than their (−)-isomer counterparts. Compounds (+)-1 and (+)-2 were found to inhibit FPT processing in COS cells at low micro molar range. They were also found to have excellent cellular antitumor activity. Evaluation of compound (+)-1 and (+)-2 in DLD-tumor model in nude mice revealed that they were efficacious, inhibiting tumor growth by 55 and 63% at 50 mpk, respectively.