Atropisomeric trihalobenzocycloheptapyridine analogues provide stereoselective FPT inhibitors with antitumor activity.
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.
Schering-Plough Research Institute, Department of Chemistry, Kenilworth, NJ 07033, USA.
F G
FG
Njoroge
B
B
Vibulbhan
W R
WR
Bishop
P
P
Kirschmeier
M S
MS
Bryant
A A
AA
Nomeir
M
M
Liu
R J
RJ
Doll
V M
VM
Girijavallabhan
A K
AK
Ganguly
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D019556:COS Cells; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D011725:Pyridines; C121493:trihalobenzocycloheptapyridine; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase