Atropisomeric trihalobenzocycloheptapyridine analogues provide stereoselective FPT inhibitors with antitumor activity

Bioorg Med Chem. 1999 May;7(5):861-7. doi: 10.1016/s0968-0896(99)00052-8.

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.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacokinetics*
  • COS Cells
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Nude
  • Models, Chemical
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacokinetics*
  • Pyridines / pharmacology*
  • Time Factors
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Pyridines
  • trihalobenzocycloheptapyridine
  • Alkyl and Aryl Transferases
  • p21(ras) farnesyl-protein transferase