Atropisomeric trihalobenzocycloheptapyridine analogues provide stereoselective FPT inhibitors with antitumor activity

Introduction of bromine at the 10-position of 3-bromo-8-chloro-benzocyclohe ptapyridine analogues of type 3 results in formation of atropisomeric compo unds of type (+/-)-1 and (+/-)-2 that are easily separable at room temperat ure on a ChiralPak(R) AD column providing pure atropisomers, (+)-1, (-)-1, and (+)-2 (-)-2, respectively. Evaluation of the FPT activity of these atro pisomers revealed that compounds (+)-1 and (+) -2 were more potent in the F PT enzyme and cellular assay than their (-)-isomer counterparts. Compounds( +)-l and (+)-2 were found to inhibit FPT processing in COS cells at low mic ro molar range. They were also found to have excellent cellular antitumor a ctivity. 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. (C) 1999 Published by Elsevier Science Ltd. A ll rights reserved.