Novel limonene phosphonate and farnesyl diphosphate analogues: design, synthesis, and evaluation as potential protein-farnesyl transferase inhibitors.
Limonene and its metabolite perillyl alcohol are naturally-occurring isoprenoids that block the growth of cancer cells both in vitro and in vivo. This cytostatic effect appears to be due, at least in part, to the fact that these compounds are weak yet selective and non-toxic inhibitors of protein prenylation. Protein-farnesyl transferase (FTase), the enzyme responsible for protein farnesylation, has become a key target for the rational design of cancer chemotherapeutic agents. Therefore, several alpha-hydroxyphosphonate derivatives of limonene were designed and synthesized as potentially more potent FTase inhibitors. A noteworthy feature of the synthesis was the use of trimethylsilyl triflate as a mild, neutral deprotection method for the preparation of sensitive phosphonates from the corresponding tert-butyl phosphonate esters. Evaluation of these compounds demonstrates that they are exceptionally poor FTase inhibitors in vitro (IC50 > or = 3 mM) and they have no effect on protein farnesylation in cells. In contrast, farnesyl phosphonyl(methyl)phosphinate, a diphosphate-modified derivative of the natural substrate farnesyl diphosphate, is a very potent FTase inhibitor in vitro (Ki=23 nM).
Eummer
J T
JT
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, Wayne State University, Detroit, MI 48202, USA.
Gibbs
B S
BS
Zahn
T J
TJ
Sebolt-Leopold
J S
JS
Gibbs
R A
RA
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D053138:Cyclohexenes; D004305:Dose-Response Relationship, Drug; D020128:Inhibitory Concentration 50; D007700:Kinetics; D000077222:Limonene; D008956:Models, Chemical; D011106:Polyisoprenyl Phosphates / Q000138:chemical synthesis* / Q000494:pharmacology; D012717:Sesquiterpenes; D013729:Terpenes / Q000138:chemical synthesis* / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D053138:Cyclohexenes; D011106:Polyisoprenyl Phosphates; D012717:Sesquiterpenes; D013729:Terpenes; C004808:farnesyl pyrophosphate; D000077222:Limonene; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase