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PubMed1999

Comamonas acidovorans strain MC1: a new isolate capable of degrading the chiral herbicides dichlorprop and mecoprop and the herbicides 2,4-D and MCPA.

A gram-negative prototrophic bacterial species, strain MC1, was isolated from the vicinity of herbicide-contaminated building rubble and identified by 16S rDNA sequence analysis, its physiological properties, GC content, and fatty acid composition as Comamonas acidovorans. This strain displays activity for the productive degradation of the two enantiomers of dichlorprop [(RS)-2-(2,4-dichlorophenoxy-)propionate; (RS)-2,4-DP] and mecoprop [(RS)-2-(4-chloro-2-methyl-) phenoxypropionate; (RS)-MCPP] in addition phenoxyacetate herbicides, i.e. 2,4-dichlorophenoxyacetate (2,4-D) and 4-chloro-2-methylphenoxyacetate (MCPA), and various chlorophenols were utilized. Rates amounted to 1.2 mmoles/h g dry mass (2,4-D) and 2.7 mmoles/h g dry mass [(RS)-2,4-DP]. Degradation of (RS)-2,4-DP was not inhibited up to concentrations of 500 mg/l, nor of 2,4-D up to 200 mg/l. The optimum pH value of (RS)-2,4-DP degradation was around 8. The application of respective primers for PCR amplification revealed the presence of tfdB and tfdC genes.

2,4-Dichlorophenoxyacetic Acid↗
PubMedDate not supplied

Estrogenic tamoxifen derivatives: categorization of intrinsic estrogenicity in MCF-7 cells.

Triarylethylenes bearing acetic acid side chains, exemplified by 4-[1-(p-hydroxyphenyl)-2-phenyl-1-butenyl]phenoxyacetic acid (4HTA), a derivative of tamoxifen (TAM), are of current interest as estrogen mimics lacking reproductive tract effects. Affinities for estrogen receptors (ER) and effects on cell growth kinetics of a diverse series of such compounds were compared with 4HTA, TAM, and with standard estrogens 17beta-estradiol (E2) and chlorotrianisene (CTA) in MCF-7 cells. These compounds exhibited concentration dependent cell growth stimulation comparable to that of CTA but less than that of E2. Growth stimulation of the more potent compounds was antagonized by TAM, signifying that effects were mediated via interaction with ER. At concentrations of 1 microM or higher, compounds with efficacies less than that of E2 were weak antagonists of estradiol-stimulated growth. Both intracellular ER affinities and growth rate stimulation potencies of the triarylethylene acetic acids and the standard ER ligands varied over a range of nearly three orders of magnitude. Analysis of growth stimulatory potency as a function of ER affinity revealed dual parallel correlations: the potency/ER affinity ratios of 4HTA and four of its analogues was about 100-fold less than those of the hydroxytriarylethane and bisphenolic analogs and the three standard ER ligands. These results suggested that ER liganded with the latter substances is more 'effective' at nuclear effector sites than is ER liganded with 4HTA and the other acidic triarylethylenes.

Breast Neoplasms↗
PubMed2001

Identification of new triarylethylene oxyalkanoic acid analogues as bone selective estrogen mimetics.

Previously, the estrogen receptor (ER) ligand 4-[1-(p-hydroxyphenyl)-2-phenylethyl]phenoxyacetic acid (5) was found to have differential bone loss suppressive effects in the ovariectomized (OVX) rat approaching those of selective ER modulators (SERMs) such as tamoxifen. In an effort to improve efficacy, analogues of this compound were prepared which incorporated features designed to reduce polarity/ionizability. Thus, the acetic acid side chain of 5 was replaced by n-butanoic acid and 1H-tetrazol-4-ylmethyl moieties, to give 8 and 10, respectively. Also, the phenolic hydroxyl of 5 was replaced, giving deoxy analogue 9. We also developed new methods for the synthesis of triarylethylene variants of 5 and 9, namely 4-([1-(p-hydroxyphenyl)-2-phenyl-1-butenyl]phenoxy)-n-butanoic acid (6) and its des-hydroxy counterpart (7), because the former of these had in vitro antiestrogenic effects characteristic of known SERMs. In the OVX rat, 6 and 7 were as effective as 17 beta-estradiol in suppressing serum markers of bone resorption/turnover, namely osteocalcin and deoxypyridinoline, but had only 30% of the uterotrophic efficacy of 17 beta-estradiol. This study has thus identified two triarylethylene oxybutyric acids, 6 and 7, that have differential bone/uterus effects like those of known SERMs.

Amino Acids↗
PubMed1989

Affinity chromatography using protein immobilized via arginine residues: purification of ubiquitin carboxyl-terminal hydrolases.

4-(Oxoacetyl)phenoxyacetic acid (OAPA) forms a stable, covalent bond between its glyoxal group and the guanidino group of arginine and arginine derivatives [Duerksen, P. J., & Wilkinson, K. D. (1987) Anal. Biochem. 160, 444-454]. Studies were carried out to determine the chemical nature of this linkage, and the structure of the stable adduct between OAPA and methylguanidine was elucidated. The stable product results from an internal oxidation-reduction of the Schiff base adduct to form a cyclic alpha-aminoamide, 4-[4-(carboxymethoxy)phenyl]-2-(methylimino)-5-oxoimidazolidine. OAPA coupled to polyacrylamide beads was used to immobilize ubiquitin via its arginine residues, and the resulting affinity support was shown to specifically and reversibly bind a previously described enzyme, ubiquitin carboxyl-terminal hydrolase [Pickart, C. M., & Rose, I. A. (1985) J. Biol. Chem. 260, 7903-7910]. The resin was then used to isolate three newly identified ubiquitin carboxyl-terminal hydrolytic activities, which did not bind to ubiquitin immobilized via lysine residues. Significant purification was achieved in each case, and one isozyme was further purified to homogeneity.

Arginine↗
PubMed1990

Lysine-329 of murine leukemia virus reverse transcriptase: possible involvement in the template-primer binding function.

Treatment of murine leukemia virus reverse transcriptase (MuLV RT) with 4-(oxoacetyl)-phenoxyacetic acid (OAPA) results in the loss of DNA polymerase as well as template-primer binding activity but has no effect on the RT-associated RNase-H activity. Binding stoichiometry revealed that approximately 3 mol of OAPA bound per mole of enzyme, when complete enzyme activation occurred. However, in the presence of template-primer, OAPA does not abolish polymerase activity and 2 mol of OAPA remains bound to 1 mol of enzyme. This observation suggests that only one OAPA reactive site is responsible for the loss of polymerase activity. This site was located on a single tryptic peptide by comparing the maps of the native enzyme and the enzyme treated with OAPA in the presence and absence of template-primer. The appearance of a new peptide peak eluting at 125 min from a C-18 reverse-phase column was consistently noted in the tryptic digest of enzyme treated with OAPA. This peak was absent in tryptic peptides made from the control enzyme or the enzyme protein that was treated with OAPA in the presence of activated DNA or synthetic template-primers. Amino acid composition and sequence analyses of this peptide revealed that it spanned residues 312-342 in the primary amino acid sequence of MuLV RT. Since this peptide does not contain arginine residues and Lys-329 exhibited resistance to tryptic digestion, we conclude that Lys-329 is the target of OAPA action.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMedDate not supplied

Reciprocal 13C-labeling: a method for investigating the catabolism of cosubstrates.

The principle of reciprocal labeling is to use a uniformly 13C-labeled substrate as the primary carbon source and a naturally labeled cosubstrate. Metabolites derived from a naturally labeled cosubstrate, in this case amino acids, can then be identified by their relatively lower content of 13C, and information on the degradation pathway can be deduced. The technique is based on GC-MS measurements of amino acid labeling patterns, making the technique well suited for investigating the relative importance of amino acid biosynthesis and amino acid uptake from the medium, as the 13C content of the amino acids incorporated into biomass is a direct measure of the amino acid biosyntheses. The technique is illustrated by the investigation of the degradation of phenoxyacetic acid, a medium component that is essential for production of penicillin V by Penicillium chrysogenum. Glucose was used as the uniformly labeled primary carbon source.

Amino Acids↗
PubMed2002

Metal ion-dependent molecular inclusion chemistry: inclusion of aromatic anions by coordinated 1,4,7,10-tetrakis((S)-2-hydroxy-3-phenoxypropyl)-1,4,7,10-tetraazacyclododecane.

The ability of the pendant donor macrocyclic ligand 1,4,7,10-tetrakis((S)-2-hydroxy-3-phenoxypropyl)-1,4,7,10-tetraaza- cyclododecane((S)-thphpc12) (or [Cd((S)-thphpc12)](2+)) to act as a metal ion-dependent receptor for aromatic anions has been investigated in solution and in the solid state. [Cd((S)-thphpc12)](2+) adopts a stable conical conformation with a large hydrophobic cavity, which has been shown to contain, via complementary multiple hydrogen bonding, p-nitrophenolate, aromatic carboxylates, p-toluenesulfonate, certain aromatic amino acid anions, phenoxyacetate, and acetate. In the case of p-nitrophenolate only, one or two anions can be contained within the receptor cavity. The crystal structure of [Cd((S)-thphpc12)(p-nitrophenolate)(2)] shows a coplanar arrangement of the p-nitrophenolates, where each is retained in the cavity by a pair of hydrogen bonds to cis hydroxyl groups. The crystal structure of the p-aminobenzoate inclusion complex indicates retention of the guest via a pair of hydrogen bonds to each oxygen atom of the carboxylate moiety. The crystal structure of the (L)-phenylalaninate inclusion complex indicates that the amino acid is retained by five hydrogen bonds, two involving the nitrogen atom and three to the oxygen atoms of the carboxylate moiety. Binding constants (10(3)-10(5) M(-1)) for the inclusion of some of the aforementioned anions in [Cd((S)-thphpc12)](2+) and related receptors were measured by (1)H NMR titration in DMSO-d(6) at 298 K.

Amino Acids↗
PubMed2006

Synthesis and characterization of water-operative cationic and anionic metal-ion activated molecular receptors for aromatic anions.

Two new, octadentate, water-soluble, macrocyclic ligands, 1,4,7,10-tetrakis((2S)-(-)-2-hydroxy-3-[3'-(N,N,N-trimethylammonium)-phenoxy]-propyl)-1,4,7,10-tetraazacyclododecane tetratriflate, ((S)-tmappc12 triflate, L1 triflate) and 1,4,7,10-tetrakis((2S)-(-)-2-hydroxy-3-[2'-sulfo-4'-methylphenoxy]-propyl)-1,4,7,10-tetraazacyclododecane, ((S)-sthmppc12, L2H4) have been prepared with a view to using them to study anion sequestration in aqueous solution. Their pKa and metal-ion binding constant values with a range of alkaline earth, transition, and post-transition metals are reported. The eight-coordinate, water-soluble Cd(II) complexes of (L1)4+ and (L2)4-, [CdL1](CF3SO3)6 and (NH4)2-[CdL2], the former cationic and the latter anionic, have both been shown to be capable of acting as anion receptors in aqueous solution. The binding constant values (log(K/M-1) given in parentheses) for binding by the cationic receptor to a range of aromatic anions in water are p-nitrophenolate (1.7), p-formylphenolate (2.1), p-nitrobenzoate (3.0), p-aminobenzoate (4.5), p-dimethylaminobenzoate (>4.5), D- and L-tryptophanate (1.6, 2.2), phenoxyacetate (2.1), and acetate (2.3). With the anionic receptor, nonzero binding constants were only measurable for p-nitrobenzoate (approximately 0.4), p-aminobenzoate (2.0), and p-dimethylaminobenzoate (1.8). By reference to the X-ray determined structures of related, but water-insoluble inclusion complexes, anion retention is thought to occur within a hydrophobic cavity, with four convergent hydroxy groups at its base, which develops in (L1)4+ and (L2)4- through the juxtapositioning of aromatic rings that occurs as a consequence of octadentate coordination.

Journal Article↗
PubMed2002

Synthesis of haptens and protein conjugates for the development of immunoassays for the insect growth regulator fenoxycarb.

Sensitive and selective enzyme-linked immunosorbent assays (ELISAs) in the immobilized antigen format were developed for fenoxycarb (1), an insect growth regulator (IGR). The parent molecule [ethyl 2-(4-phenoxyphenoxy)ethylcarbamate] was derivatized at several positions to obtain haptens (2-5) that were used to produce protein conjugates and rabbit polyclonal antisera. Amino derivatives of fenoxycarb at the terminal and internal rings (2 and 3, respectively) were linked to carrier proteins by azo coupling. Carboxyalkyl-spacer groups were attached to the ethyl group and the nitrogen atom of the target compound (1) to obtain haptens 4 and 5, respectively. Hapten-homologous ELISAs based on protein conjugates of compounds 2 and 4 determined fenoxycarb in the mid-ppb range (IC(50), 102 and 95 ppb, respectively). A more sensitive hapten-heterologous ELISA (IC(50), 17 ppb; detection limit 0.5 ppb) involved the antiserum raised against a conjugate of hapten 2 and the plate-coating antigen obtained from compound 3. These assays displayed no significant interferences with photodegradation products of fenoxycarb, the IGRs methoprene and pyriproxyfen, and a variety of pesticides including the pyrethroids fenvalerate and cypermethryn, the phenoxyacetic acid herbicide 2,4-D, DDT, and the nitrodiphenyl ether herbicides acifluorfen and fluorodifen.

Animals↗
PubMed2002

Enzyme-linked immunosorbent assay for the pyrethroid deltamethrin.

A competitive enzyme-linked immunosorbent assay (ELISA) for the detection of deltamethrin was developed. Two haptens, cyano[3-(4-aminophenoxy)phenyl]methyl 1R-cis-3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarboxylate and 3-[(+/-)-cyano[1R-cis-3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropan ecarbonyloxy]methyl]phenoxyacetic acid, were synthesized and conjugated with thyroglobulin as immunogens. Four antisera were generated and screened against six different coating antigens. The assay that was the most sensitive for deltamethrin was optimized and characterized. The I(50) for deltamethrin was 17.5 +/- 3.6 microg/L, and the lower detection limit was 1.1 +/- 0.5 microg/L. This ELISA assay had relatively low cross-reactivities with other major pyrethroids, such as permethrin, phenothrin, bioresmethrin, cyfluthrin, and cypermethrin. Methanol was found to be the best organic cosolvent for this ELISA, with optimal sensitivity observed at a concentration of 40% (v/v). The assay parameters were unchanged at pH values between 5.0 and 8.0, whereas higher ionic strengths strongly suppressed the absorbances. To increase the sensitivity of the overall method, a C(18) sorbent-based solid-phase extraction was used for river water samples. River water samples fortified with deltamethrin were analyzed according to this method. Good recoveries and correlation with spike levels were observed.

Animals↗
PubMed2004

Development of an enzyme-linked immunosorbent assay for the pyrethroid cypermethrin.

A competitive enzyme-linked immunosorbent assay (ELISA) for the detection of cypermethrin was developed. Two haptens, the trans- and cis-isomers of 3-[(+/-)-cyano-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyloxy]methyl]phenoxyacetic acid, were conjugated with thyroglobulin as immunogens. Four antisera were generated and screened against six different coating antigens. The assay that was the most sensitive for cypermethrin was optimized and characterized. The IC(50) for cypermethrin was 13.5 +/- 4.3 microg/L, and the lower detection limit (LDL) was 1.3 +/- 0.5 microg/L. This ELISA had relatively low cross-reactivities with other major pyrethroids, such as deltamethrin, phenothrin, resmethrin, fluvalinate, and permethrin. Methanol was found to be the best organic cosolvent for this ELISA, with an optimal sensitivity observed at a concentration of 40% (v/v). The assay parameters were unchanged at pH values between 5.0 and 8.0, whereas higher ionic strengths strongly suppressed the absorbances. To increase the sensitivity of the overall method, a C(18) sorbent-based solid-phase extraction was applied to various domestic and environmental water samples. The water samples, fortified with cypermethrin, were analyzed according to this method. Good recoveries and correlation with spike levels were observed.

Enzyme-Linked Immunosorbent Assay↗
PubMed2004

Metabolism of diethofencarb (isopropyl 3,4-diethoxyphenylcarbamate) in rats: identification of metabolites in urine.

Rats were orally given a diethofencarb (isopropyl 3,4-diethoxyphenylcarbamate) labeled with (14)C, at 300 mg/kg/day, for 4 consecutive days, and 11 metabolites in urine were purified by a combination of several chromatographic techniques. The chemical structures of all isolated metabolites were identified by spectroanalyses (NMR and MS). Ten of them were newly identified forms. Five of them were S-conjugates: three mercapturic acid conjugates, one S-methyl conjugate, and one SO-methyl conjugate. The others were two phenoxyacetic acids, hydroxyacetanilide, hydroxyisopropyl carbamate, and oxazolinone derivatives. From the results, the existence of the following reactions in rats can be concluded: (1) deethylation of the 4-ethoxy group; (2) conjugation of phenols with glutathione, gamma-glutamyltranspeptidation and depeptidation of the glutathione to form cysteine conjugates, and N-acetylation of the cysteine; (3) cleavage of the C-S linkage of cysteine conjugates followed by methylation; (4) oxidation of the S-methyl group; (5) cleavage of the carbamate linkage; (6) acetylation of the resultant amino group; (7) oxidation of the acetyl group; (8) oxidation of the isopropyl group; (9) cyclization of the oxidized isopropyl carbamate group; and (10) oxidation of the 4-ethoxy group.

Animals↗
PubMed2006

Studies on water transport through the sweet cherry fruit surface. 11. FeCl3 decreases water permeability of polar pathways.

The effect of FeCl3 (10 mM) on osmotic water uptake into detached sweet cherry fruit (Prunus avium L.) and on the (3)H2O permeability (P(d)) of excised exocarp segments (ES) or enzymatically isolated cuticular membranes (CM) was investigated. ES or CM were mounted in an infinite dose diffusion system, where diffusion is monitored from a dilute donor solution through an interfacing ES or CM into a receiver solution under quasi steady-state conditions. In the absence of FeCl3, (3)H2O diffusion through stomatous ES was linear over time, indicating that P(d) was constant. Adding FeCl3 to the donor decreased P(d) by about 60%. P(d) remained at a decreased level when replacing the FeCl3 donor again by deionized water. The decrease in P(d) was positively and linearly related to the stomatal density of the ES. There was no effect of FeCl3 on the P(d) of astomatous sweet cherry fruit ES or CM regardless of the presence of wax (epicuticular or cuticular). FeCl3 decreased P(d) when added to the donor (-63%) or receiver (-16%), but there was no effect when it was added to donor and receiver solutions simultaneously. The decrease in P(d) depended on the pH of the receiver and the presence of citrate buffer. There was no effect of FeCl3 with citrate buffer as a receiver regardless of pH (range 2.0-6.0). When using nonbuffered receiver solutions with pH adjusted to pH 2.0, 3.0, 4.5, or 6.0, FeCl3 markedly decreased (3)H2O diffusion at pH > or = 3 but had no effect at pH 2.0. FeCl3 increased the energy of activation (E(a)) for (3)H2O diffusion (range 15-45 degrees C) through stomatous ES but had no significant effect in astomatous CM. The increase in E(a) by FeCl3 was positively related to stomatal density. FeCl3 decreased the P(d) for 2-(1-naphthyl)[1-(14)C]acetic acid (NAA) and 2,4-dichloro[U-(14)C]phenoxyacetic acid (2,4-D) in stomatous ES. The magnitude of the effect depended on the degree of dissociation and was larger for the dissociated acids (pH 6.2) than for the nondissociated acids (pH 2.2). Incubating whole fruit in isotonic solutions of selected osmotica resulted in significant water uptake that was inversely related to the molecular weight of the osmotica and was consistently lower for fruit treated with FeCl3. The FeCl3 induced decrease in water fluxes was larger for osmotica having a low molecular weight than for those with a higher molecular weight. Our data indicate that FeCl3 decreased the permeability of the stomatous sweet cherry exocarp to water and other polar substances by pH-dependent formation of precipitates that decrease transport along polar pathways. Decreasing the permeability of polar pathways by a precipitation reaction is a useful target in developing strategies against rain-induced fruit cracking.

Biological Transport↗
PubMed1992

Low molecular weight, non-peptide fibrinogen receptor antagonists.

The tetrapeptide H-Arg-Gly-Asp-Ser-OH (1) (RGDS), representing a recognition sequence of fibrinogen for its platelet receptor GP IIb-IIIa (integrin alpha IIb beta 3), served as lead compound for the development of highly potent and selective fibrinogen receptor antagonists. Replacement of the N-terminal arginine by p-amidinophenylalanine or the Gly moiety by m-aminobenzoic acid led to compounds which are superior to the lead peptide with regard to activity and selectivity for GP IIb-IIIa vs the closely related vitronectin receptor alpha v beta 3. By random screening [(p-amidinobenzenesulfonamido)ethyl]-p-phenoxyacetic acid derivatives have been identified as fibrinogen receptor antagonists. Further structure-activity relationship studies culminated in the preparation of N-[N-[N-(p-amidinobenzoyl)-beta-alanyl]-L-alpha-aspartyl]-3-phenyl-L- alanine (29h, Ro 43-5054) and [[1-[N-(p-amidinobenzoyl)-L-tyrosyl]-4-piperidinyl]oxy]acetic acid (37f, Ro 44-9883), which exhibit very high activity as platelet aggregation inhibitors (IC50s 0.06 and 0.03 microM, respectively, human PRP/ADP) as well as marked selectivity for GP IIb-IIIa vs alpha v beta 3. Since the activity of 37f in dogs declines according to a two-compartment model with an initial phase having a t1/2 of 8 min and a second phase with a t1/2 of 110 min, this compound is a suitable candidate for the development as iv platelet inhibitor.

Amino Acid Sequence↗
PubMed1978

Diuretic activity of Mannich base derivatives of ethacrynic acid and certain ethacrynic acid analogues.

Various Mannich base derivatives of selected phenoxyacetic acid type diuretics were synthesized and their diuretic potency was evaluated in dogs. It is concluded that the Mannich bases possess little, if any, diuretic activity of their own. Those Mannich bases that do possess diuretic activity undoubtedly do so as a consequence of an elimination reaction (a retro-Michael type reaction) which yields the corresponding pharmacologically active alpha,beta-unsaturated ketone.

Animals↗
PubMed1975

Hypocholesteremic derivatives of styrylacetic acid. 1. gem-Dimethyl analogs of benzalbutyric acid.

The preparation of alpha, alpha-dimethyl analogs of the hypocholesteremic and hypolipemic agent 3-methyl-4-phenyl-3-butenoic acid (beta-benzalbutyric acid, BBA) is described. These compounds were prepared as part of a continuing program directed toward a study of the structure-activity interrelationships of styryl- and phenoxyacetic acid antilipemic agents and the preparation of metabolically resistant analogs of BBA. Preliminary results on the in vitro ability of the compounds to inhibit cholesterol biosynthesis indicate that alpha, alpha-dimethyl substitution reduces activity although the potency of the p-chloro analog 6b was comparable to that of BBA.

Acetates↗
PubMed2002

Highly antibacterial active aminoacyl penicillin conjugates with acylated bis-catecholate siderophores based on secondary diamino acids and related compounds.

New acylated bis-catecholates and 1,3-benzoxazine-2,4-dione derivatives based on secondary diamino acids (N-(aminoalkyl)glycines, N-aminopropyl-alanine, and N-aminopropyl-4-aminovaleric acid), on N-(aminoalkyl)aminomethyl benzoic acids, on N-(aminoalkyl)aminomethyl phenoxyacetic acids, or on 3,5-diaminobenzoic acid were synthesized as artificial siderophores. The corresponding diamino acids were obtained from the diamines and oxocarboxylic acids by catalytic hydrogenation. The acylated bis-catecholates and 1,3-benzoxazine-2,4-diones were coupled with ampicillin or amoxicillin to new siderophore aminoacylpenicillin conjugates. These conjugates exhibited very strong antibacterial activity in vitro against Gram-negative bacterial pathogens including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Escherichia coli, Klebsiella pneumoniae, and Serratia marcescens. The ampicillin derivative 7b (HKI 9924154) and the corresponding amoxicillin derivative 8 (HKI 9924155) represent the most active compounds. The conjugates can use bacterial iron siderophore uptake routes to penetrate the Gram-negative outer membrane permeability barrier. This was demonstrated by assays with mutants deficient in components of the iron transport systems. New siderophore penicillin V conjugates with the siderophore component attached to the phenyl ring of penicillin V are inactive against these Gram-negative bacteria.

Amino Acids↗
PubMed2005

Synthesis, biological evaluation, and three-dimensional quantitative structure-activity relationship study of small-molecule positive modulators of adrenomedullin.

Adrenomedullin (AM) is a peptide hormone implicated in blood pressure regulation and in the pathophysiology of several diseases such as hypertension, cancer, diabetes, and renal disorders, becoming an interesting new target for the development of drugs. In a recent high-throughput screening study, a positive modulator with a bistriazole structure has been identified.(1) In this work, a new series of structurally related compounds has been synthesized by reaction of phenoxyacetic acid with the corresponding dihydrazide, followed by treatment of the formed bisoxadiazoles with benzylamine. The affinity toward AM of the lead compound, and a structurally related family obtained from the small-molecule NCI library together with the synthesized series, has been determined. A three-dimensional quantitative structure-activity relationship (3D-QSAR) study and conformational and molecular dynamics simulations have shown that the presence of a free NH and a phenyl group is essential for the interaction of these compounds with AM.

Adrenomedullin↗