Atropisomeric trihalobenzocycloheptapyridine analogues provide stereoselective FPT inhibitors with antitumor activity

Abstract

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.