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PubMed2003

Validation of liquid chromatography assay for the quantitation of (Z)-3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]propionic acid (SU006668) in human plasma and its application to a phase I clinical trial.

The validation of an analytical method to quantify the antiangiogenic, (Z)-3-[2,4-dimethyl-5-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrol-3-yl]propionic acid (SU006668) for pharmacokinetic determination in a phase I clinical trial, is described. HPLC, with a gradient mobile phase and UV detection at 440 nm, was used. SU006668 was extracted from plasma by precipitation of proteins with acetonitrile. The assay was linear from 25 to 2000 ng/ml (r(2)=0.997); sensitive (limit of quantification 25 ng/ml), accurate (RE 2.6-11.9%) and reproducible (inter-batch precision C.V. 3.2%). Pharmacokinetic data for six patients are presented. They show linear pharmacokinetics with a low volume of distribution and induction at doses of 50, 100 and 200 mg/m(2).

Antineoplastic Agents↗
PubMed2002

Gas-phase analysis of trimethylamine, propionic and butyric acids, and sulfur compounds using solid-phase microextraction.

Complaints due to odors are an important problem for the wastewater, composting, and animal agriculture industries. Accurate, objective measurement techniques are needed to monitor emissions, to develop new waste handling procedures, and to reduce the production of these volatile gases. Solid-phase microextraction was investigated as a technique for the determination of representative odorous gases. A flow-through Teflon chamber was used to expose the fibers to certified gas standards. A 75-microm carboxen-poly(dimethylsiloxane) (Car-PDMS) coating was used for trimethylamine (TMA), carbon disulfide (CS2), dimethylsulfide (DMS), and dimethyl disulfide (DMDS), and an 85-microm polyacrylate coating was used for propionic acid (PA) and butyric acid (BA). Using a 1-h fiber exposure time and a flow rate through the chamber of 72 mL/min, method detection limits were 2.38, 0.074, 0.150, 0.063, 1.85, and 1.32 ppbv for TMA, DMS, CS2, DMDS, PA, and BA, respectively. Enhanced detector signal was observed for all analytes under flow conditions, as compared to static conditions, and the porous nature of the Car-PDMS coating appears to increase the time needed for analytes to reach equilibrium under flow conditions.

Adsorption↗
PubMed2002

New functionalization of myoglobin by chemical modification of heme-propionates.

The reconstitution of myoglobin with an artificially created prosthetic group is a unique method for introducing a new chemical function into the protein. Particularly, the modification of two heme-propionates gives us an effective binding domain or binding site on the protein surface. This Account traces the design and construction of the highly ordered binding domain around the entrance of the heme pocket. The discussion includes the protein-small molecule or protein-protein recognition, electron transfer reaction within the complex, and enhancement of the chemical reactivity of the myoglobin with a substrate binding site. The synthetic approach to modifying a protein will be a new trend in engineering a novel function in naturally occurring hemoprotein.

Binding Sites↗
PubMed2000

Discovering new enzymes and metabolic pathways: conversion of succinate to propionate by Escherichia coli.

The Escherichia coli genome encodes seven paralogues of the crotonase (enoyl CoA hydratase) superfamily. Four of these have unknown or uncertain functions; their existence was unknown prior to the completion of the E. coli genome sequencing project. The gene encoding one of these, YgfG, is located in a four-gene operon that encodes homologues of methylmalonyl CoA mutases (Sbm) and acyl CoA transferases (YgfH) as well as a putative protein kinase (YgfD/ArgK). We have determined that YgfG is methylmalonyl CoA decarboxylase, YgfH is propionyl CoA:succinate CoA transferase, and Sbm is methylmalonyl CoA mutase. These reactions are sufficient to form a metabolic cycle by which E. coli can catalyze the decarboxylation of succinate to propionate, although the metabolic context of this cycle is unknown. The identification of YgfG as methylmalonyl CoA decarboxylase expands the range of reactions catalyzed by members of the crotonase superfamily.

Amino Acid Sequence↗
PubMed2002

Enantiomeric resolution of 2-aryl propionic esters with hyperthermophilic and mesophilic esterases: contrasting thermodynamic mechanisms.

The enantiomeric resolution of 2-aryl propionic esters by hyperthermophilic and mesophilic esterases was found to be governed by contrasting thermodynamic mechanisms. Entropic contributions predominated for mesophilic esterases from Candida rugosa and Rhizomucor miehei, while enthalpic forces controlled this resolution by the esterase from the extremely thermoacidophilic archaeon, Sulfolobus solfataricus P1. This disparity in thermodynamic mechanism can be attributed to the differences in conformational flexibility of mesophilic and thermophilic enzymes as they relate to the temperature range (4-70 degrees C) examined.

Candida↗
PubMed2005

Enantioselective radical addition/trapping reactions with alpha,beta-disubstituted unsaturated imides. Synthesis of anti-propionate aldols.

This manuscript describes a highly diastereo- and enantioselective intermolecular radical addition/hydrogen atom transfer to alpha,beta-disubstituted enoates. Additionally, we show that anti-propionate aldol-like products can be easily prepared from alpha-methyl-beta-acyloxyenoates in good yields and high diastereo- and enantioselectivities.

Aldehydes↗
PubMed2006

Catalytic asymmetric assembly of stereodefined propionate units: an enantioselective total synthesis of (-)-pironetin.

Double diastereoselection in alkaloid-catalyzed acyl halide-aldehyde cyclocondensation (AAC) reactions provides a strategy for realizing syn- or anti-selective propionate aldol additions from a common reaction manifold. Matched AAC homologation of enantioenriched aldehydes afford cis-disubstituted beta-lactones as surrogates for syn aldols; the mismatched AAC reactions provide anti-selective aldols in the form of trans-disubstituted 2-oxetanones. The utility of this reaction technology in synthesis activities is exemplified in a catalytic asymmetric total synthesis of (-)-pironetin.

Antineoplastic Agents↗
PubMed1992

Development of a novel series of styrylquinoline compounds as high-affinity leukotriene D4 receptor antagonists: synthetic and structure-activity studies leading to the discovery of (+-)-3-[[[3-[2-(7-chloro-2-quinolinyl)-(E)-ethenyl]phenyl][[3- (dimethylamino)-3-oxopropyl]thio]methyl]thio]propionic acid.

Based on LTD4 receptor antagonist activity of 3-(2-quinolinyl-(E)-ethenyl)pyridine (2) found in broad screening, structure-activity studies were carried out which led to the identification of 3-[[[3-[2-(7-chloro-2-quinolinyl)-(E)-ethenyl]phenyl][[3- (dimethylamino)-3-oxopropyl]thio]methyl]thio]propionic acid (1, MK-571) as a potent and orally active LTD4 receptor antagonist. These studies demonstrated that a phenyl ring could replace the pyridine in 2 without loss of activity, that 7-halogen substitution in the quinoline group was optimal for binding, that the (E)-ethenyl linkage was optimal, that binding was enhanced by incorporation of a polar acidic group or groups in the 3-position of the aryl ring, and that two acidic groups could be incorporated via a dithioacetal formed from thiopropionic acid and the corresponding styrylquinoline 3-aldehyde to yield compounds such as 20 (IC50 = 3 nM vs [3H]LTD4 binding to the guinea pig lung membrane). It was found that one of the acidic groups could be transformed into a variety of the amides without loss of potency and that the dimethylamide 1 embodied the optimal properties of intrinsic potency (IC50 = 0.8 nM on guinea pig lung LTD4 receptor) and oral in vivo potency in the guinea pig, hyperreactive rat, and squirrel monkey. The evolution of 2 to 1 involves the increase of > 6000-fold in competition for [3H]LTD4 binding to guinea pig lung membrane and a > 40-fold increase in oral activity as measured by inhibition of antigen-induced dyspnea in hyperreactive rats.

Animals↗
PubMed1990

Stereospecific synthesis, assignment of absolute configuration, and biological activity of the enantiomers of 3-[[[3-[2-(7-chloroquinolin-2-yl)-(E)-ethenyl]phenyl] [[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]propionic acid, a potent and specific leukotriene D4 receptor antagonist.

The enantiomers of the leukotriene D4 antagonist 3-[[[3-[2-(7-chloroquinolin-2-yl)-(E)-ethenyl]phenyl] [[3-(dimethylamino)-3-oxopropyl]thio]methyl]thio]propionic acid (L-660,711)(MK-571) have been prepared, their absolute stereochemistry has been assigned as S for (+)-1 and R for (-)-1 by X-ray analysis of a synthetic intermediate (5), and the biological activity of the enantiomers has been explored. Unexpectedly, the enantiomers are both comparably biologically active with (+)-1 slightly more intrinsically active at the LTD4 receptor in vitro.

Animals↗
PubMed1978

Resolution of antimalarial agents via complex formation with alpha-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy) propionic acid.

The resolution of several antimalarial agents via pi-complex formation with alpha-(2,4,5,7-tetranitro-9-fluorenylideneaminooxy) propionic acid (TAPA) is reported. Since this represents the first use of this agent for the resolution of amines, some details of the separations are presented. The method proved successful for resolving weakly alkaline amines that did not form stable salts with common resolving acids, highly insoluble amines that did not form soluble salts with usual resolving acids, and amines that did not form crystalline salts with commonly available resolving acids. The optical isomers of several antimalarial agents were evaluated against Plasmodium berghei in the mouse. None of the optically active forms showed any significant differences. The curative activity of (+)- and (-)-primaquine against Plasmodium cynomolgi in the rhesus monkey was essentially identical; however, significant differences in toxicity were noted.

Animals↗
PubMed2001

Design and synthesis of 2-methyl-2-[4-(2-[5-methyl-2-aryloxazol-4-yl]ethoxy)phenoxy]propionic acids: a new class of dual PPARalpha/gamma agonists.

Propionic acid derivative 8, which was designed and synthesized based on putative pharmacophores of known PPARgamma- and PPARalpha-selective compounds, exhibits potent dual PPARalpha/gamma agonist activity as demonstrated by in vitro binding and dose overlap in the newly introduced EOB mouse model for glucose lowering and lipid/cholesterol homeostasis.

Animals↗
PubMed2002

II. Synthesis and biological evaluation of some bioisosteres and congeners of the antitumor agent, 2-(4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469).

XK469 (1) is among the most highly and broadly active antitumor agents to have been evaluated in our laboratories. Subsequent developmental studies led to the entry of (R)-(+) 1 (NSC 698215) into phase 1 clinical trials (NIH UO1-CA62487). The antitumor mechanism of action of 1 remains to be elucidated, which has prompted a sustained effort to elaborate a pharmacophoric pattern of 1. The present study focused on a strategy of synthesis and biological evaluation of topologically based, bioisosteric replacements of the quinoxaline moiety in the lead compound (1) by quinazoline (4a-d), 1,2,4-benzotriazine (12a-18b), and quinoline (21a-g) ring systems. The synthetic approach to each of the bioisosteres of 1 utilized the methodology developed in previous work (see Hazeldine, S. T.; Polin, L.; Kushner, J.; Paluch, J.; White, K.; Edelstein, M.; Palomino, E.; Corbett, T. H.; Horwitz, J. P. Design, Synthesis, and Biological Evaluation of Analogues of the Antitumor Agent 2-(4-[(7-Chloro-2-quinoxalinyl)oxy]phenoxy)propionic acid (XK469). J. Med. Chem. 2001, 44, 1758-1776.), which is extended to the procurement of the benzoxazole (23a,b), benzthiazole (23c,d), pyridine (25a,b), and pyrazine (27) congeners of 1. Only quinoline analogues, bearing a 7-halo (21a,b,d,e) or a 7-methoxy substituent (21g), showed antitumor activities (Br > Cl > CH(3)O > F approximately I), at levels comparable to or greater than the range of activities manifested by 1 and corresponding analogues. At high individual dosages, the (S)-(-) enantiomers of 1 and 21b,d all produce a reversible slowing of nerve-conduction velocity in the mice, the onset of which is characterized by a distinctive dysfunction of the hind legs, causing uncoordinated movements. The condition resolves within 5-10 min. However, at higher dosages, which approach a lethal level, the behavior extended to the front legs, lasting from 20 min to 1 h. By contrast, the (R)-(+) forms of these same agents did not induce the phenomenon of slowing of nerve-conduction velocity.

Animals↗
PubMed2003

Rational design, synthesis, and structure-activity relationships of novel factor Xa inhibitors: (2-substituted-4-amidinophenyl)pyruvic and -propionic acids.

An inhibitor of factor Xa (fXa), the m-substituted benzamidine AXC1578 (1a), was structurally modified with the aim of increasing its potency. In particular, pyruvic acid and propionic acid substituents were incorporated into the P1 benzamidine moiety to introduce a favorable interaction with the oxy-anion hole in the catalytic triad region of fXa. This strategy was based on computational docking studies using the extracted active site of fXa. The validity of the computational model was supported by the acquisition of X-ray crystal structures of the 1a-trypsin and 3b-trypsin complexes (the homology around the active sites of fXa and trypsin is high). The above modifications significantly increased the inhibitory activity toward fXa, whereas the high selectivity for fXa versus thrombin was maintained or enhanced. Compounds 3b, 3c, 3e, and 4b are considered to be potential lead compounds for the development of orally active anticoagulant drugs because they demonstrated potent activity when administered orally to cynomolgus monkeys.

Administration, Oral↗
PubMed2004

Synthesis and conformational studies of dipeptides constrained by disubstituted 3-(aminoethoxy)propionic acid linkers.

A series of cyclic compounds with dimethyl-substituted 3-(aminoethoxy)propionic acid linkers have been prepared as potential beta-turn mimics. The desired linkers were prepared from disubstituted pyrones, which were coupled with dipeptides and then subjected to macrocyclization using diethylcyanophosphonate to furnish cyclic compounds 1-5. Conformational analysis was carried out using NMR and X-ray crystallography. All of the five cyclic compounds were found to exist in type I or type II beta-turn conformations.

Cross-Linking Reagents↗
PubMed2004

A concise asymmetric synthesis of (2S,3S,7S)-3,7-dimethylpentadecan-2-yl Acetate and propionate, the sex pheromones of pine sawflies.

(2S,3S,7S)-3,7-Dimethylpentadecan-2-yl acetate (2) and its propionate analogue (3) are the main sex pheromones of all Neodiprion species and Diprion similes, respectively. Starting from (S)-malic acid and employing a highly chemo-, regio-, and stereoselective tandem ester reduction-epoxide formation-reductive epoxide-opening reaction protocol, an efficient total synthesis of (2S,3S,7S)-2 and -3 is reported herein.

Acetates↗
PubMed2003

Placidenes C-F, novel alpha-pyrone propionates from the Mediterranean sacoglossan Placida dendritica.

Four new alpha-pyrone-containing propionates (5-8) and an unprecedented hydroperoxide 9 have been isolated from the mantle extract of Placida dendritica, a Mediterranean sacoglossan that lives upon the green alga Bryopsis plumosa. The new metabolites co-occur with the related compounds 1-4, which have been described in previous studies of the mollusc. The presence of 9 opens intriguing perspectives on the ecological role of placidenes. This paper reports the isolation and structural elucidation of the new compounds 5-9.

Animals↗
PubMed2003

CCR5 antagonists: 3-(pyrrolidin-1-yl)propionic acid analogues with potent anti-HIV activity.

[reaction: see text] A novel approach to alpha,alpha-disubstituted-beta-amino acids (beta(2,2)-amino acids) was employed in the synthesis of a series of 3-(pyrrolidin-1-yl)propionic acids possessing high affinity for the CCR5 receptor and potent anti-HIV activity. The rat pharmacokinetics for these new analogues featured higher bioavailabilities and lower rates of clearance as compared to cyclopentane 1.

Anti-HIV Agents↗