Robert Patton

A cembranolide diterpene farnesyl protein transferase inhibitor from the marine soft coral Lobophytum cristagalli

Abstract A previously described cembranolide diterpene from Lobophytum cristagalli was identified as a potent (IC50 0.15 μM) inhibitor of farnesyl protein transferase (FPT). The compound showed selectivity for FPT as compared to the closely related enzyme geranylgeranyl protein transferase-1 (IC50 5.3 μM). Kinetic evaluation suggests that this compound competes with the protein/peptide farnesyl acceptor substrate, and not with farnesyl pyrophosphate for inhibition of FPT.

SCH 58450, a novel farnesyl protein transferase inhibitor possessing a 6a,12a:7,12-diepoxybenz[a]anthracene ring system

SCH 58450, a novel secondary metabolite possessing the 6a,12a:7,12.diepoxybenz[a]anthracene ring system, has been isolated from a Streptomyces sp. SCH 58450 inhibits farnesyl protein transferase with an IC50 of 29 μM, and shows 25 fold selectivity for farnesyl protein transferase over geranylgeranyl protein transferase-1.

Analogues of 1-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo-[5,6]-cyclohepta [1,2-b]pyridin-11-yl)piperidine as inhibitors of farnesyl protein transferase.

The synthesis of several 4-pyridylacetyl N-oxide derivatives of 4-(3-bromo-6,11-dihydro-5H-benzo[5,6]-cyclohepta[1,2-b]-pyridin-11-yl)pi perazine/piperidine 3 is described. This study was aimed at identifying fomesyl protein transferase (FPT) inhibitors in these two series of tricycles containing different phenyl ring substituents. The in vitro activity profile of the initial group of compounds 7a-7g led to the synthesis of the 8-methyl-10-methoxy and 8-methyl-10-bromo analogues 7i, 13i, and 13j. The 11R(-) enantiomers of these compounds were found to exhibit potent in vitro FPT inhibition activity.

Synthesis of 5,6-dihydro-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidine-N-cyanoguanidine derivatives as inhibitors of ras farnesyl protein transferase.

A series of novel N-cyanoguanidine tricyclic farnesyl protein transferase (FPT) inhibitors was prepared. Replacement of a piperidine amide-group with a N-cyanoguanidine functionality increased FPT activity. X-ray crystal structure determination of 42 complexed with FPT revealed differences in the interactions of the amide and N-cyanoguanidine groups with the protein.

Sch 207278: a novel farnesyl protein transferase inhibitor from an unidentified fungus

Abstract Novel aromatic dialdehyde, Sch 207278 (1), was isolated from an unidentified fungus as an inhibitor of farnesyl protein transferase (FPTase). The structure of 1 was elucidated by spectroscopic methods. Compound 1 exhibited an IC50 value of 3.5 μM against FPTase and 70 μM against geranylgeranyl protein transferase-1 (GGPTase-1), respectively.