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At least 19 recordsLinked to original sources
PubMed1993

Synthesis and biological evaluation of cholecystokinin analogs in which the Asp-Phe-NH2 moiety has been replaced by a 3-amino-7-phenylheptanoic acid or a 3-amino-6-(phenyloxy)hexanoic acid.

Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester (JMV180), an analog of the C-terminal octapeptide of cholecystokinin (CCK-8), shows interesting biological activities behaving as an agonist at the high-affinity CCK binding sites and as an antagonist at the low-affinity CCK binding sites in rat pancreatic acini. Although we did not observe any major hydrolysis of the ester bond of Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester in our in vitro studies, we were aware of a possible and rapid cleavage of this ester bond during in vivo studies. To improve the stability of Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester, we decided to synthesize analogs in which the ester bond would be replaced by a carba (CH2-CH2) linkage. We synthesized the 3-amino-7-phenylheptanoic acid (beta-homo-Aph) with the R configuration in order to mimic the Asp-2-phenylethyl ester moiety and the 3-amino-6-(phenyloxy)hexanoic acid (H-beta-homo-App-OH), an analog of H-beta-homo-Aph-OH in which a methylene group has been replaced by an oxygen. (R)-beta-Homo-Aph and (R)-H-beta-homo-App-OH were introduced in the CCK-8 sequence to produce Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-(R)-beta-homo-Aph-OH and Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-(R)-beta-homo-App-OH. Both compounds were able to recognize the CCK receptor on rat pancreatic acini (IC50 = 12 +/- 8 nM and 13 +/- 5 nM, respectively), on brain membranes (IC50 = 32 +/- 2 nM and 57 +/- 5 nM, respectively), and on Jurkat T cells (IC50 = 75 +/- 15 nM and 65 +/- 21 nM, respectively). Like Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester, both compounds produced maximal stimulation of amylase secretion (EC50 = 6 +/- 2 nM and 4 +/- 2 nM, respectively) with no decrease of the secretion at high concentration indicating that these compounds probably act as agonists at the high-affinity peripheral CCK-receptor and as antagonists at the low-affinity CCK-receptor. Replacing the tryptophan by a D-tryptophan in such analogs produced full CCK-receptor antagonists. All these analogs might be more suitable for in vivo studies than Boc-Tyr(SO3H)-Nle-Gly-Trp-Nle-Asp-2-phenylethyl ester.

Amino Acid Sequence↗
PubMedDate not supplied

Synthesis of two photoreactive heterobifunctional reagents derived from hexanoic acid.

The synthesis of two photoreactive heterobifunctional reagents derived from hexanoic acid is described. The compounds are succinimido 6-N-(4-azidobenzoyl)aminohexanoate (1c) and succinimido 6-mercapto-S-(4-azidothiophenyl)hexanoate (2c). Compound 1c was synthesized from benzyloxycarbonyl 4-aminobenzoic acid and 6-aminohexanoic acid benzyl ester. Compound 2c was obtained by disulfide exchange of dithiobis-4-aminobenzene with 6-mercaptohexanoic acid. The azido function was introduced by displacement of the corresponding diazonium salt and the active ester, by the mixed anhydride method. Both compounds were decomposed by ultraviolet irradiation. Phytohemagglutinin was modified by reaction with reagent 1c or 2c. Irradiation afforded polymeric lectin derivatives resulting from intermolecular cross-linking. Sodium dodecyl sulfate--polyacrylamide gel electrophoresis analyses revealed the presence of Coomasie-positive bands of molecular weight 33000, 67000, 120000, 144000, and higher. Polymeric structures resulting from irradiation of phytohemagglutinin modified with compound 2c were cleaved by reduction with 2-mercaptoethanol or with dithiothreitol. Phytohemagglutinin modified by reaction with compound 1c or 2c retained its ability to stimulate pig spleen lymphocytes in vitro. Whereas the lectin treated with reagent 2c was active as the unmodified protein, the lectin treated with compound 1c was more active than unmodified lectin at nearly all the concentrations tested.

Animals↗
PubMed2000

Development of an attractant for the scarab pest Macrodactylus subspinosus (Coleoptera: Scarabaeidae).

Field trials were conducted over several seasons to determine the attractant most successful in luring adult rose chafers, Macrodactylus subspinosus (F.), to traps. During the first season, 20 compounds were compared with the standard lure, valeric acid + hexanoic acid + octyl butyrate (1:1:1). The two new standards establishedthat season were: valeric acid + 1-nonanol (1:1); and valeric acid + hexanoic acid + octyl butyrate + 1-nonanol (1:1:1:1). The following season, 36 compounds were evaluated, comparing them to the new standards. The performance of the standard binary lure valeric acid + 1-nonanol was improved when the alcohol 1-nonanol was replaced by its analog trans-2-nonenol and this was confirmed during the third season. At the same time, a second test was conducted with 29 new candidates, which were combined with valeric acid and compared with the standard: valeric acid + hexanoic acid + octyl butyrate + 1-nonanol (1:1:1:1). A control and the single compound alpha-ionone were included, resulting in the discovery of a new more powerful attractant, alpha-ionone. Testing of alpha-ionone continued the following season, at which time the initial leading candidate and new ones containing trans-2-nonenol were tested against the single attractant alpha-ionone and various combinations of it. A new five-component mixture of valeric acid, hexanoic acid, octyl butyrate, trans-2-nonenol, and alpha-ionone out performed all other lure combinations.

Animals↗
PubMedDate not supplied

[Radiosensitization of human tumor HeLa cells induced by methyl ester of 6-oxo-6-[2,2-ethylenedioxy-5-(dimethoxycarbonylmethyl)-cyclope nt- 1-yL]-hexanoic acid].

Methyl ester of 6-oxo-6-[2,2-ethylenedioxy-5-(dimethoxycarbonylmethyl)- cyclopent-1-yl]-hexanoic acid (7-keto-9,9-ethylenedioxiprostanoid, that is analogue of 11-deoxy-PGE1 with modified chains) at concentration 10(-6) mol/l displayed maximal (25%) sensitizing effect when was tested in a range of concentrations 10(-7)-10(-5) mol/l and HeLa cells were gamma-irradiated at dose of 2 Gy, that was compared with metronidazol action. Optimal time of prostanoid contact with cells was between 30 and 60 min, and metronidazol--60 min. Prostanoid effect was exhibited at irradiation doses from 2 to 4 Gy and reached maximum of 46% at 4 Gy, its DMF was 1.5 as well as that of metronidazol. Cytotoxicity of comparable compounds was approximately equal. By its chemical structure and sensitizing features this 7-keto-9,9-ethylenedioxiprostanoid is a prototype of new radiosensitizing drug.

Alprostadil↗
PubMed2007

Development and validation of high-performance liquid chromatography-tandem mass spectrometry assay for 6-(3-benzoyl-ureido)-hexanoic acid hydroxyamide, a novel HDAC inhibitor, in mouse plasma for pharmacokinetic studies.

A liquid chromatography/tandem mass spectrometric method for the quantification of 6-(3-benzoyl-ureido)-hexanoic acid hydroxyamide (EX-2), a novel histone deacetylase (HDAC) inhibitor, in mouse plasma was developed to support in-house pharmacokinetic (PK) studies in the lead optimization stage. In order to determine the PK parameters for EX-2 in comparison to other HDAC inhibitors such as suberoylanilide hydroxamic acid (SAHA), PXD-101 and LBH-589, which are currently in different stages of clinical trials, research-grade bio-analytical method validations were carried out for EX-2 and these reference HDAC inhibitors, which were synthesized by in-house medicinal chemists. The components of validation consisted of specificity, extraction efficiency, signal-response of calibration standards, lower limit of quantification, autosampler stability and accuracy and precision of quality control samples. The validated LC/MS/MS methods were accurate and precise. The calibration curve ranged from 1 to 1600 ng/mL for all the analytes. The methods developed were used to quantify EX-2 and other HDAC inhibitors in mouse plasma obtained from pharmacokinetic studies. The results suggest that EX-2 has better PK parameters compared with the reference drugs and is a promising drug development candidate.

Animals↗
PubMed2006

Quantitating the dynamics of NBD hexanoic acid in homogeneous solution and in solutions containing unilamellar vesicles.

We report here on the motional and fluorescence lifetime dynamics of the chromophore NBDHA (6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid) in neat solvents and in aqueous solutions containing unilamellar vesicles of varying composition. We measure the transient response of this chromophore by time-correlated single-photon counting, using one- and two-photon excitation to resolve the Cartesian components of the rotational diffusion constant, D. Our experimental data for NBDHA in selected solvents of varying viscosity demonstrate that one- and two-photon excitation probe different components of the rotational diffusion constant and that this chromophore reorients as a prolate rotor with an aspect ratio of approximately 2. For NBDHA in aqueous solutions containing unilamellar vesicles of varying composition, we recover the same reorientation behavior regardless of vesicle composition. Fluorescence lifetime and steady-state fluorescence data show the chromophore to reside in a polar environment that is different from neat water. We understand these data in the context of the chromophore residing in close proximity to the unilamellar vesicle polar headgroups in all cases.

Caproates↗
PubMed1993

Evidence against the formation of 2-amino-6-(2-formyl-5-hydroxymethyl-pyrrol-1-yl)-hexanoic acid ('pyrraline') as an early-stage product or advanced glycation end product in non-enzymic protein glycation.

1. It has been suggested that 2-amino-6-(2-formyl-5-hydroxymethyl-pyrrol-1-yl)-hexanoic acid ('pyrraline') is formed as an advanced glycation end product in the Maillard reaction under physiological conditions. Antibodies were raised to caproyl-pyrraline linked to keyhole-limpet haemocyanin and were used to develop an e.l.i.s.a. and Western blotting system for the specific detection of pyrraline in samples in vivo and in vitro. 2. Human serum albumin was isolated from the serum samples of diabetic and non-diabetic subjects. Pyrraline was not detected (< 1.2 pmol) in any of the samples, indicating that it was not a major advanced glycation end product in vivo. 3. BSA was incubated separately with D-glucose and a model fructosamine, N epsilon-(1-deoxy-D-fructos-1-yl)-hippuryl-lysine, under physiological conditions for 30 days. Aliquots removed from the incubations at 5 day intervals contained no detectable pyrraline, indicating that pyrraline was not an early-stage product of the Maillard reaction in vitro. 4. The model fructosamine, N epsilon-(1-deoxy-D-fructos-1-yl)-hippuryl-lysine, was incubated at pH 7.4 and 37 degrees C for 25 days during which it degraded to hippuryl-lysine and N epsilon-carboxymethyl-hippuryl-lysine. Aliquots were removed at 5 day intervals and assayed for pyrraline. None was detected (< 23 pmol/ml) in the course of the degradation of the fructosamine (400 nmol/ml degraded), indicating that pyrraline was not a major product of the degradation of fructosamine under physiological conditions in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Regio- and stereo-selectivity in the induction of peroxisome proliferation by substituted hexanoic acids.

Quantitative structure-activity relationship is an effective tool in order to predict drug potency. A similar approach is actually developed for peroxisome proliferation induced by substituted carboxylic acids issued from plasticizer metabolism in rats. The study is focused on acids found in rat urine after adipic diester dosings. Size, location of the substituted group and length of the chain have been studied. 3-D structure has also been taken in account for 2-ethyl hexanoic acids. The results obtained so far demonstrate that peroxisome proliferation potencies of the considered acids are modified according structure changes. At this time location of the group along the chain appears to be a predominant factor.

Animals↗
PubMed2006

A fluoro analogue of the menadione derivative 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl]hexanoic acid is a suicide substrate of glutathione reductase. Crystal structure of the alkylated human enzyme.

Glutathione reductase is an important housekeeping enzyme for redox homeostasis both in human cells and in the causative agent of tropical malaria, Plasmodium falciparum. Glutathione reductase inhibitors were shown to have anticancer and antimalarial activity per se and to contribute to the reversal of drug resistance. The development of menadione chemistry has led to the selection of 6-[2'-(3'-methyl)-1',4'-naphthoquinolyl]hexanoic acid, called M(5), as a potent reversible and uncompetitive inhibitor of both human and P. falciparum glutathione reductases. Here we describe the synthesis and kinetic characterization of a fluoromethyl-M(5) analogue that acts as a mechanism-based inhibitor of both enzymes. In the course of enzymatic catalysis, the suicide substrate is activated by one- or two-electron reduction, and then a highly reactive quinone methide is generated upon elimination of the fluorine. Accordingly the human enzyme was found to be irreversibly inactivated with a k(inact) value of 0.4 +/- 0.2 min(-1). The crystal structure of the alkylated enzyme was solved at 1.7 A resolution. It showed the inhibitor to bind covalently to the active site Cys58 and to interact noncovalently with His467', Arg347, Arg37, and Tyr114. On the basis of the crystal structure of the inactivated human enzyme and stopped-flow kinetic studies with two- and four-electron-reduced forms of the unreacted P. falciparum enzyme, a mechanism is proposed which explains naphthoquinone reduction at the flavin of glutathione reductase.

Animals↗
PubMed1983

Characterization of imidazo[1,5-a]pyridine-5-hexanoic acid (CGS 13080) as a selective thromboxane synthetase inhibitor using in vitro and in vivo biochemical models.

CGS 13080 inhibited cell-free thromboxane synthetase with an IC50 of 3 nM. It was at least five orders of magnitude less potent toward other key enzymes involved in arachidonic acid metabolism. Submicromolar concentrations inhibited calcium ionophore-induced formation of thromboxane B2 by intact human platelets with concomitant accumulation of prostaglandin E2. Oral doses lower than 1 mg/kg in rats suppressed the elevations of plasma thromboxane B2 induced by calcium ionophore. This was attended by shunting of endoperoxide substrate to 6-keto-prostaglandin F1 alpha and prostaglandin E2. CGS 13080 is one of the most potent and selective thromboxane synthetase inhibitors yet identified.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

Derivatives of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline: effect of changes at positions 2 and 5 of the hexanoic acid portion.

Several derivatives of the potent angiotensin converting enzyme inhibitor 5(S)-benzamido-4-oxo-6-phenylhexanoyl-L-proline (1) were synthesized and tested for converting enzyme inhibition activity and blood pressure lowering effects in rats. One compound, 5(S)-benzamido-2(R)-methyl-4-oxo-6-phenylhexanoyl-L-proline (2a), had and I50 against angiotensin converting enzyme of 1.0 x 10(-9) M and is the most potent inhibitor prepared thus far in this class of compounds. Testing of 2a orally at 30 mg/kg for inhibition of the angiotensin I induced blood pressure increase in conscious normotensive rats gave 100% inhibition that required 143 min before the angiotensin I blood pressure response returned to 70% of the pretreatment control response. In the conscious renal hypertensive rat, 2a given orally at a dose of 3 mg/kg caused a lowering of blood pressure that reached its maximum of 40 mmHg 8 h following drug administration.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1987

Thromboxane synthase inhibitors. Synthesis and pharmacological activity of (R)-, (S)-, and (+/-)-2,2-dimethyl-6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)- methoxy]methyl]ethoxy]hexanoic acids.

A series of substituted omega-[2-(1H-imidazol-1-yl)ethoxy]alkanoic acid derivatives were synthesized and evaluated for their ability to inhibit thromboxane synthase both in vitro and in vivo. Compound 13 was identified as a potent and selective competitive inhibitor of human platelet thromboxane synthase having a Ki value of 9.6 X 10(-8) M. In collagen-treated human whole blood, 13 potentiated levels of 6-keto PGF1 alpha. Enantiospecific syntheses afforded the R and S enantiomers of 13, of which the S enantiomer 13b was the more potent. Compounds 13 and 13b were potent in vivo inhibitors of thromboxane synthase with good oral activity and duration of action.

6-Ketoprostaglandin F1 alpha↗