30337-09-8Relevant academic research and scientific papers
Inhibitors of farnesyl protein transferase
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, (2008/06/13)
Inhibition of farnesyl transferase, which is an enzyme involved in ras oncogene expression, and inhibition of cholesterol biosynthesis, are effected by compounds of the formula STR1 their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs, and solvates, wherein: x is --ONR1 C(O)--, --N(OR1)C(O)--, --NR1 C(O)--, --C(O)NR1 --, --NR1 S(O2)--, --C(O)O--, --OC(O)--, --C(O)--, --O--, --NR1 -- or --(S)q --; Y is --CO2 R2, --SO3 R2 or --P(O) (OR2) (R3); R is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkenylene or aryl; R3 is --(O)t R4 ; R1, R2 and R4 are each independently hydrogen, alkyl, aryl or aralkyl; m and n are each independently 0 or an integer from 1 to 5; p and t are each independently 0 or 1; and q is an integer from 1 to 2.
Farnesyl Diphosphate-Based Inhibitors of Ras Farnesyl Protein Transferase
Patel, Dinesh V.,Schmidt, Robert J.,Biller, Scott A.,Gordon, Eric M.,Robinson, Simon S.,Manne, Veeraswamy
, p. 2906 - 2921 (2007/10/02)
The rational design, synthesis, and biological activity of farnesyl diphosphate (FPP)-based inhibitors of the enzyme Ras farnesyl protein transferase (FPT) is described.Compound 3, wherein a β-carboxylic phosphonic acid type pyrophosphate (PP) surrogate is connected to the hydrophobic farnesyl group by an amide linker, was found to be a potent (I50(FPT) = 75 nM) and selective inhibitor of FPT, as evidenced by its inferior activity against squalene synthetase (I50(SS) = 516 μM) and mevalonate kinase (I50(MK) = >200 μM).A systematic structure-activity relationship study involving modifications of the farnesyl group, the amide linker, and the PP surrogate of 3 was undertaken.Both the carboxylic and phosphonic acid groups of the β-carboxylic phosphonic acid PP surrogate are essential for activity, since deletion of either group results in 50-2600-fold loss in activity (6-9, I50 = 4.6-220 μM).The farnesyl group also displays very stringent requirements and does not tolerate one carbon homologation (12, I50 = 17.7 μM), substitution by a dodecyl fragment (14, I50 = 9 μM), or introduction of an extra methyl group at the allylic position (18, I50 = 55 μM).Modifications around the amide linker group of 3 were more forgiving, as evidenced by the activity of N-methyl analog (21, I50 = 0.53 μM), the one carbon atom shorter farnesoic acid-derived retroamide analog (32, I50 = 250 nM), and the exact retroamide analog (49, I50 = 50 nM).FPP analogs such as 3, 32, and 49 are novel, potent, selective, small-sized, nonpeptidic inhibitors of FPT that may find utility as antitumor agents.
31P NMR-Structure Correlations for Phosphonocarboxylic Acids and Esters
Olagnon-Bourgeot, Sabine,Chastrette, Francine,Wilhelm, Dider
, p. 971 - 976 (2007/10/03)
31P chemical shift-structure correlations were established from methyl and ethyl esters of simple phosphonocarboxylic acids.The influence of solvent, acidity, function and neighbourhood of phosphorus was studied.The correlations could be extended and led to the identification of esters obtained when a series of phosphonocarboxylic acids were reacted with alcohols-reactions which were designed as models of cellulose cross-linking by these acids. - Key words: NMR; 31P NMR; structure-δ correlations; phosphonocarboxylic acid esters; esterification
Effect of Phosphono Substituents on Acyl Transfer Reactions
Shames, Spencer L.,Byers, Larry D.
, p. 6177 - 6184 (2007/10/02)
The rate of release of p-nitrophenoxide from esters of phosphono-substituted carboxylic acids was examined as a function of pH(D), temperature, divalent metal ion (Mg2+ and Ca2+) concentration, and acyl acceptor (-OH and the thiolate of N-acetylcysteine).The hydrolysis of p-nitrophenyl 3-phosphonopropionate involves intramolecular nucleophilic catalysis by the dianionic phosphono substituent (pKa2(*) = 7.5) and is characterized by a first-order rate constant of 94 min-1 at 37 deg C.A comparison of the rate constant of the unimolecular reaction with that of the corresponding bimolecular reaction (corrected for the inductive effect of the acyl substituent and for the phosphonate basicity) yields a rate constant ratio of kuni/kbi = 7(+/-6)*103 M.The magnitude of this rate enhancement is similar to those of analogous intramolecular reactions (e.g., hydrolysis of mono-p-nitrophenyl succinate or of p-nitrophenyl 4-(N,N-dimethylamino)butyrate but, unlike these reactions, the rate acceleration resulting from intramolecular nucleophilic catalysis by the dianionic phosphono group is enthalpic in origin (Δ(*) ca. 8 kcal/mol).The entropy of activation for the intramolecular reaction is less favorable than that for the bimolecular reaction (Δ(*) ca. 9 eu).The alkaline hydrolysis and the thiolysis rates of p-nitrophenyl phosphonoacetate are accelerated over 100-fold by the association of Mg2+ or Ca2+ with the ester.This rate acceleration is attributed to the formation of a six-membered bidentate coordination complex between the divalent cation and the incipient tetrahedral intermediate.The metal-promoted acyl transfer reactions of p-nitrophenyl phosphonoacetate provide a convenient system for the quantitative assessment of the role of metal ions in the catalysis of aqueous reactions.
