R115777 (Zarnestra) is a farnesyl protein transferase inhibitor currently undergoing worldwide clinical trials. As acquired drug resistance may limit the efficacy of the drug, a model of acquired resistance has been established in vitro by continuous drug exposure of the human colon cancer cell line KM12. A stably resistant cell line possessing 13-fold resistance to R115777 was generated. The r...

Modification of GTPases with isoprenoid molecules derived from geranylgeranyl pyrophosphate or farnesyl pyrophosphate is an essential requisite for cellular signaling pathways. The synthesis of these isoprenoids proceeds in mammals through the mevalonate pathway, and the final steps in the synthesis are catalyzed by the related enzymes farnesyl pyrophosphate synthase and geranylgeranyl pyrophos...

Ras proteins play fundamental roles in cell signal transduction pathways that regulate cell growth, differentiation, proliferation, and survival. ras mutations are among the most frequently encountered genetic abnormalities in human cancers and play a key role in tumorigenesis. The enzymatic attachment of a 15- or 20-carbon moiety to the Ras protein through farnesylation or geranylgeranylation,...

To access P1-farnesyl-P2-indicator diphosphates, more efficient methods for the synthesis of farnesyl-phosphate and diphosphates were developed. The procedures reported here provide more flexible conditions than the conventional imidazolide and morpholidate coupling methods. Milder conditions for the synthesis of sensitive allylic diphosphates and greatly improved reaction efficiencies provide ...

Long chain cis-prenyltransferase in rat liver microsomes was studied using various allylic isoprenoid substrates. Microsomes could utilize trans-geranyl pyrophosphate, but not cis-geranyl pyrophosphate for polyprenyl pyrophosphate synthesis. Both trans, trans-farnesyl pyrophosphate and trans,cis-farnesyl pyrophosphate were used as substrates with Km values of 24 and 5 microM, respectively. tran...

It has long been known that small changes to the structure of the R(2) side chain of nitrogen-containing bisphosphonates can dramatically affect their potency for inhibiting bone resorption in vitro and in vivo, although the reason for these differences in antiresorptive potency have not been explained at the level of a pharmacological target. Recently, several nitrogen-containing bisphosphonat...

Recent studies on cholesterol biosynthesis have demonstrated that the biosynthesis of squalene from its immediate precursor, farnesyl pyrophosphate, is accompanied by the exchange of 1 hydrogen atom at C-l, in 1 of the 2 precursor molecules, for a hydride ion derived from reduced triphosphopyridine nucleotide (l-3). Thus, Popjak et al. obsrrved that the farnesol of farnesyl pyrophosphate biosyn...

This study aimed to identify the chemical composition (ash, cellulose, total chlorophylls, carotenoid, and essential oil (EO) content), antioxidant activity, mineral of lemon balm (Melissa officinalis L) obtained from Bulgaria. The EO was analyzed using gas chromatography-mass spectrometry (GC-MS). major constituents were caryophyllene oxide (33.99%), n-hexadecanoic acid (14.28%), α-citral (6.6...

Thiolo thiophosphate analogues of isopentenyl diphosphate (IPP), dimethylallyl diphosphate (DMAPP), geranyl diphosphate (GPP), farnesyl diphosphate (FPP), and geranylgeranyl diphosphate (GGPP) were synthesized. Inorganic thiopyrophosphate (SPP(i)) was prepared from trimethyl phosphate in four steps. The tris(tetra-n-butylammonium) salt was then used to convert isopentenyl tosylate to (S)-isopen...

1. Hoover RR, Mahon FX, Melo JV, Daley GQ. Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336. Blood. 2002;100:1068-1071. 2. O’Connell M, Wolfinger R. Spatial regression models, response surfaces and process optimization. J Comput Graph Statist. 1997;6:224-241. 3. Shi B, Yaremko B, Hajian G, et al. The farnesyl protein transferase inhibitor SCH66336 synergizes with ta...