ABSTRACT
In breast cancer cells expressing c-Src and EGFR, a control of one of the two oncogenes over proliferation and invasion is observed, whereas in others, the synergistic interaction between them is required for tumor progression. With the purpose of developing molecules with the highest probability for blocking the adverse effects of these two oncogenes, we designed AL622, which contains a quinazoline head targeted to EGFR and a linker that bridges it to the PP2-like structure for targeting c-Src. In case the entire molecule would not be capable of blocking c-Src, we designed AL622 to hydrolyze to an intact c-Src-targeting PP2 molecule. After confirming its binary c-Src-EGFR targeting potency of AL622, we analyzed its potency in isogenic NIH3T3 cells transfected with EGFR and HER2 and human breast cancer cells known to be dominated by c-Src function. The results showed that in EGFR/HER-2-driven cells, it was more potent than PP2 and its activity was in the same range as the latter in more c-Src-driven cells. Its ability to block motility and invasion was comparable with that of PP2 and corresponding combinations, indicating that AL622 could be a better antitumor agent in cells where c-Src and/or EGFR play a role.
Subject(s)
Adenine/analogs & derivatives , ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Quinazolines/chemistry , src-Family Kinases/antagonists & inhibitors , Adenine/chemical synthesis , Adenine/chemistry , Adenine/toxicity , Animals , CSK Tyrosine-Protein Kinase , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Drug Design , ErbB Receptors/metabolism , Humans , Kinetics , Mice , NIH 3T3 Cells , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/toxicity , Quinazolines/chemical synthesis , Quinazolines/toxicity , src-Family Kinases/metabolismABSTRACT
Access to P-chiral H-phosphinates via desymmetrization of hypophosphite esters was investigated. The use of chiral auxiliaries, chiral catalysts, and of a bulky prochiral group that could lead to kinetic resolution was explored. A chiral NMR assay for enantiomeric excess determination of H-phosphinates was developed. An asymmetric route to C-chiral H-phosphinates is also examined and an assay was developed.
Subject(s)
Esters/chemical synthesis , Organophosphonates/chemistry , Catalysis , Molecular Structure , StereoisomerismABSTRACT
The preparation and reactivity of some α,α-difluorophosphinates is investigated. Alkylation of H-phosphinates with LiHMDS and ClCF(2)H gives the corresponding α,α-difluorophosphinates in good yield. Deprotonation of these reagents with alkyllithium or LDA is then studied. Subtle electronic effects translate into significant differences in the deprotonation/alkylation of the two "Ciba-Geigy reagents" (EtO)(2)CRP(O)(OEt)H (R = H, Me). On the other hand, attempted methylation of difluoromethyl-octyl-phosphinic acid butyl ester resulted in the exclusive alkylation of the octyl chain. Finally, reaction with carbonyl compounds results in the formation of 1,1-difluoro-2-phosphinoyl compounds.
ABSTRACT
Protein farnesyltransferase (FTase) has recently appeared as a new target of parasitic diseases, a field poor in drugs in development. With the aim of creating new bisubstrate inhibitors of FTase, new farnesyl pyrophosphate analogues have been studied. Farnesyl analogues with a malonic acid function exhibited the best inhibitory activity on FTase. This group was introduced into our imidazole-containing model leading to new compounds with submicromolar activities. Kinetic experiments have been realized to determine their binding mode to the enzyme.
Subject(s)
Farnesyltranstransferase/antagonists & inhibitors , Polyisoprenyl Phosphates/chemical synthesis , Polyisoprenyl Phosphates/pharmacology , Sesquiterpenes/chemical synthesis , Sesquiterpenes/pharmacology , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Kinetics , Molecular Structure , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Plasmodium falciparum/growth & development , Polyisoprenyl Phosphates/chemistry , Sesquiterpenes/chemistry , Stereoisomerism , Structure-Activity Relationship , Trypanosoma brucei brucei/drug effects , Trypanosoma brucei brucei/growth & developmentABSTRACT
The design, synthesis, and evaluation of a series of novel inhibitors of aspartate transcarbamoylase (ATCase) are reported. Several submicromolar phosphorus-containing inhibitors are described, but all-carboxylate compounds are inactive. Compounds were synthesized to probe the postulated cyclic transition-state of the enzyme-catalyzed reaction. In addition, the associated role of the protonation state at the phosphorus acid moiety was evaluated using phosphinic and carboxylic acids. Although none of the synthesized inhibitors is more potent than N-phosphonacetyl-l-aspartate (PALA), the compounds provide useful mechanistic information, as well as the basis for the design of future inhibitors and/or prodrugs.
Subject(s)
Aspartate Carbamoyltransferase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Aspartate Carbamoyltransferase/metabolism , Aspartic Acid/analogs & derivatives , Aspartic Acid/chemistry , Binding Sites/drug effects , Biocatalysis/drug effects , Drug Evaluation, Preclinical , Enzyme Inhibitors/metabolism , Enzyme Stability/drug effects , Escherichia coli/enzymology , Models, Chemical , Phosphonoacetic Acid/analogs & derivatives , Phosphonoacetic Acid/chemistry , Structure-Activity RelationshipABSTRACT
With the aim of creating new bisubstrate inhibitors of protein farnesyltransferase (FTase), new carboxylic farnesyl pyrophosphate analogues have been designed and synthesized. The original structures are built around three elements: a prenyl moiety, a 1,4-diacid motif and an imidazole ring. All the compounds were evaluated for their ability to inhibit FTase and compared with the corresponding derivatives lacking the imidazole ring, synthesized for that purpose. These new compounds are not bisubstrate inhibitors probably because the imidazole ring is not in the right position to interact with the zinc atom. However these derivatives display FPP competitive inhibition with a good activity in the carboxylic farnesyl pyrophosphate analogues series.
Subject(s)
Enzyme Inhibitors , Farnesyltranstransferase/antagonists & inhibitors , Imidazoles , Polyisoprenyl Phosphates , Pyrans , Sesquiterpenes , Animals , Cell Line, Tumor , Cell Survival/drug effects , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Inhibitory Concentration 50 , Mice , Molecular Structure , Nitric Oxide/biosynthesis , Polyisoprenyl Phosphates/chemical synthesis , Polyisoprenyl Phosphates/chemistry , Polyisoprenyl Phosphates/pharmacology , Pyrans/chemical synthesis , Pyrans/chemistry , Pyrans/pharmacology , Sesquiterpenes/chemical synthesis , Sesquiterpenes/chemistry , Sesquiterpenes/pharmacologyABSTRACT
The design, syntheses, and enzymatic activity of two submicromolar competitive inhibitors of aspartate transcarbamoylase (ATCase) are described. The phosphinate inhibitors are analogs of N-phosphonacetyl-l-aspartate (PALA) but have a reduced charge at the phosphorus moiety. The mechanistic implications are discussed in terms of a possible cyclic transition-state during enzymatic catalysis.
Subject(s)
Aspartate Carbamoyltransferase/chemistry , Chemistry, Pharmaceutical/methods , Enzyme Inhibitors/pharmacology , Escherichia coli/enzymology , Aspartic Acid/analogs & derivatives , Aspartic Acid/chemistry , Binding, Competitive , Catalysis , Colorimetry/methods , Drug Design , Enzyme Inhibitors/chemistry , Escherichia coli Proteins/chemistry , Kinetics , Models, Chemical , Phosphonoacetic Acid/analogs & derivatives , Phosphonoacetic Acid/chemistry , Phosphorus/chemistry , Protein ConformationABSTRACT
H-Phosphinates obtained through various methodologies are protected directly via reaction with triethyl orthoacetate. The resulting products can be manipulated easily, and various synthetic reactions are presented. For example, application to the synthesis of aspartate transcarbamoylase (ATCase) or kynureninase inhibitors are illustrated. Other reactions, such as Sharpless' asymmetric dihydroxylation, or Grubbs' olefin cross-metathesis are also demonstrated.
ABSTRACT
A novel catalytic allylation of H-phosphinic acids is described. Using Pd/xantphos (2 mol %), H-phosphinic acids react directly with allylic alcohols to produce P-allylated disubstituted phosphinic acids.
Subject(s)
Palladium/chemistry , Phosphinic Acids/chemistry , Propanols/chemistry , CatalysisABSTRACT
The reactions of phosphinylidene-containing compounds with unactivated unsaturated hydrocarbons are reviewed. The review is organized by phosphorus-containing functional group types. Free-radical and metal-catalyzed additions of R(1)R(2)P(O)H to alkenes, alkynes, and related compounds, deliver functionalized organophosphorus compounds RP(O)R(1)R(2), including H-phosphinates, phosphinates, tertiary phosphine oxides, and phosphonates. The review covers the literature up to February 2008.
ABSTRACT
Benzylic alcohols cross-couple directly with concentrated H(3)PO(2) using Pd/xantphos (1 or 2 mol-%). Depending on the substrate, DMF at 110°C, or t-AmOH at reflux with a Dean-Stark trap, can be used. A broad range of benzylic alcohols reacted successfully in moderate to good yields. The preparation of other organophosphorus compounds (phosphinic and phosphonic acids) is also demonstrated.Asymmetric reaction with (R)-1-(2-naphthyl)ethanol provided the corresponding H-phosphinic acid in 77% ee. The methodology provides a green, PCl(3)-free, entry into benzylic-H-phosphinic acids.
ABSTRACT
A novel approach to H-phosphonates from hypophosphorous acid using a transfer hydrogenation process was developed. This method is atom-economical, environmentally friendly, catalytic, and efficient, leading easily to H-phosphonate monoesters or ammonium salt in moderate to good yields.
ABSTRACT
A novel series of compounds, derived from 2,5-functionalized imidazoles, have been synthesized as potential bisubstrate inhibitors of protein farnesyltransferase (FTase) using structure-based design. These compounds have a 1,4-diacid chain and a tripeptide connected by an imidazole ring. The synthetic strategy relies on the functionalization at the C-2 position of the heterocycle with the diacid side chain and peptide coupling at the C-5 position. Several new compounds were synthesized in good yields. Kinetic experiments on the most active compounds revealed different binding modes depending on the diacid chain length.