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PubMed1991

Anisotropy decays of indole, melittin monomer and melittin tetramer by frequency-domain fluorometry and multi-wavelength global analysis.

We used frequency-domain fluorescence spectroscopy to measure the fluorescence lifetime and anisotropy decays of indole in propylene glycol, and of the tryptophan emission of melittin monomer and tetramer in water solutions at 5 degrees C. We obtained an increase in resolution of the anisotropy decays by using multiple excitation wavelengths, chosen to provide a range of fundamental anisotropy values. The multi-excitation wavelength anisotropy decays were analyzed globally to recover a single set of correlation times with wavelength-dependent anisotropy amplitudes. Simulated data and kappaR2 surfaces are shown to reveal the effect of multi-wavelength data on the resolution of complex anisotropy decays. For both indole and melittin, the anisotropy decays are heterogeneous and require two correlation times to fit the frequency-domain data. For indole in propylene glycol at 5 degrees C we recovered correlation times of 0.59 and 4.10 ns, which appear to be characteristic of the rigid and asymmetric indole molecule. For melittin monomer the correlation times were 0.13 and 1.75 ns, and for melittin tetramer 0.12 and 3.96 ns. The shorter and longer correlation times of melittin are due to segmental motions and overall rotational diffusion of the polypeptide.

Journal Article↗
PubMed2007

Prediction of indolent prostate cancer: validation and updating of a prognostic nomogram.

PURPOSE: Screening with serum prostate specific antigen testing leads to the detection of many prostate cancers early in their natural history. Statistical models have been proposed to predict indolent cancer. We validated and updated model predictions for a screening setting. MATERIALS AND METHODS: We selected 247 patients with clinical stage T1C or T2A from the European Randomized Study on Screening for Prostate Cancer who were treated with radical prostatectomy. We validated a nomogram that had previously been developed in a clinical setting. Predictive characteristics were serum prostate specific antigen, ultrasound prostate volume, clinical stage, prostate biopsy Gleason grade, and total length of cancer and noncancer tissue in biopsy cores. Indolent cancer was defined as pathologically organ confined cancer 0.5 cc or less in volume without poorly differentiated elements. Logistic regression was used to update the previous model and examine the contribution of other potential predictors. RESULTS: Overall 121 of 247 patients (49%) had indolent cancer, while the average predicted probability was around 20% (p <0.001). Effects of individual variables were similar to those found before and discriminative ability was adequate (AUC 0.76). An updated model was constructed, which merely recalibrated the nomogram and did not apply additional predictors. CONCLUSIONS: Prostate cancers identified in a screening setting have a substantially higher likelihood of being indolent than those predicted by a previously proposed nomogram. However, an updated model can support patients and clinicians when the various treatment options for prostate cancer are considered.

Aged↗
PubMed2001

Selection of fungal elicitors to increase indole alkaloid accumulation in catharanthus roseus suspension cell culture.

Various fungal elicitors derived from 12 fungi were tested to improve indole alkaloid production in Catharanthus roseus cell suspension cultures. Results show that different fungal mycelium homogenates stimulate different kinds of indole alkaloid (ajmalicine, serpentine and catharanthine) accumulation, which ranged from 2- to 5-fold higher than the control. Some fungal culture filtrates also efficiently elicited the biosynthesis of different indole alkaloids. The optimal elicitor addition and exposure time for the maximal alkaloid production were on day 7 after subculture and for 3 days of treatment but different fungal elicitors showed the different optimal treatment dosages. Additions of elicitor at the doses ranging from 5 mg/l to 30 mg/l of carbon hydrate equivalent resulted in varieous amounts and kinds of indole alkaloid accumulation. Exposed to a same fungal elicitor, several different cell lines generated the different responses regarding as growth rate, culture color and alkaloid production.

Journal Article↗
PubMed1988

Sensitive determination of deuterated and non-deuterated indole-3-acetic acid and 5-hydroxyindole-3-acetic acid by combined capillary gas chromatography-negative-ion chemical ionization mass spectrometry.

Sensitive methods for the determination of deuterated and non-deuterated indole-3-acetic acid and 5-hydroxyindole-3-acetic acid by combined capillary gas chromatography-negative-ion chemical ionization mass spectrometry were developed. Indole-3-acetic and 5-hydroxyindole-3-acetic acids were converted into pentafluorobenzyl and trifluoroacetylmethyl derivatives, respectively, after pre-purification by high-performance liquid chromatography. These derivatives were separated by gas chromatography and determined by selected ion monitoring. In the determinations, indole-3-acetic-2,2,2',4',5',6',7'-d7 acid and 5-hydroxyindole-3-acetic-3,3-d2 acid were used as internal standards. The methods developed in this work were used for the determination of deuterated and non-deuterated indole-3-acetic acid and 5-hydroxyindole-3-acetic acid in human urine samples collected before and after administration of L-tryptophan-3,3-d2.

Adult↗
PubMed2000

Effect of water-soluble vitamins on the production of indole-3-acetic acid by Azospirillum brasilense.

The effects of six water-soluble vitamins on tryptophan-dependent synthesis of indole-3-acetic acid in Azospirillum brasilense were investigated. A multifactorial regression analysis was employed to produce models of indole-3-acetic acid synthesis versus concentrations of tryptophan and the vitamins added to the growth medium. Very low levels of the B-group vitamins added at 10 to 100 microg l(-1) affected production of indole-3-acetic acid in A. brasilense. The largest release of this phytohormone was observed after amendment with pyridoxine and nicotinic acid. Results of the study suggest a role these vitamins may fulfil in the regulation of indole-3-acetic acid synthesis in A. brasilense.

Azospirillum brasilense↗
PubMed1988

Mechanistic deductions from multiple kinetic and solvent deuterium isotope effects and pH studies of pyridoxal phosphate dependent carbon-carbon lyases: Escherichia coli tryptophan indole-lyase.

Analysis of the pH dependence of the kinetic parameters and competitive inhibitor Ki values for tryptophan indole-lyase suggests two enzymic groups must be unprotonated in order to facilitate binding and catalysis of tryptophan. The V/K for tryptophan and the pKi for oxindolyl-L-alanine, a putative transition state analogue and competitive inhibitor, decrease below two pK values of 7.6 and 6.0, while the Ki for L-alanine, also a competitive inhibitor, is 3300-fold larger (20 mM) than that for oxindolyl-L-alanine and increases below a single pK of 7.6. A single pK of 7.6 is also observed in the V/K profile for the alternate substrate, S-methyl-L-cysteine. Therefore, the enzymic group with a pK of 7.6 is responsible for proton abstraction at the 2-position of tryptophan, while the enzymic group with a pK of 6.0 interacts with the indole portion of tryptophan and probably catalyzes formation of the indolenine tautomer of tryptophan (in concert with proton transfer to C-3 of indole from the group with pK 7.6) to facilitate carbon-carbon bond cleavage and elimination of indole. The pH variation of the primary deuterium isotope effects for proton abstraction at the 2-position of tryptophan (DV = 2.5 and D(V/Ktrp) = 2.8) are pH independent, while the Vmax for tryptophan or S-methyl-L-cysteine is the same and also pH independent. Thus, substrates bind only to the correctly protonated form of the enzyme. Further, tryptophan is not sticky, and the pK values observed in both V/K profiles are the correct ones.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗
PubMed2005

A tryptophan-containing open-chain framework for tuning a high selectivity for Ca2+ and 13C NMR observation of a Ca2+-indole interaction in aqueous solution.

Two molecular architectures featuring the cation-responsive tryptophan indole were designed and investigated for the development of a novel fluorescent chemosensor for Ca2+. We observed that the Trp-based open-framework chemosensor EW2 exhibits remarkable selectivity for Ca2+ over Mg2+, Ba2+, K+, Na+, and Li+ in water between pH 4.6 and 7.0 on the basis of Ca2+-induced high fluorescence enhancement of the Trp residue. A combined 13C NMR and CD spectroscopic study has demonstrated a dynamic reorientation of the indole ring due to the cation-indole interaction accompanying the Ca2+-induced dramatic fluorescence enhancement. The results suggest that the highly sensitive, metal-ion-dependent Trp indolyl C(3) chemical shifts may serve as a promising indicator for monitoring metal ion-indole noncovalent interaction in solution.

Calcium↗
PubMed1990

Nonsteroidal cardiotonics. 3. New 4,5-dihydro-6-(1H-indol-5-yl)pyridazin-3(2H)-ones and related compounds with positive inotropic activities.

A series of substituted indolyldihydropyridazinones and related compounds 1-18 were synthesized and evaluated for positive inotropic activity. In rats, most of these indole derivatives produced a dose-related increase in myocardial contractility with little effect on heart rate and blood pressure. Compound 13, 4,5-dihydro-5-methyl-6-(2-pyridin-4-yl-1H-indol-5-yl)pyrazin-3(2H) -one (BM 50.0430), was further investigated in cats. The increase in contractility in this animal model was not mediated via stimulation of beta-adrenergic receptors. After oral administration of 1 mg/kg to conscious dogs, compound 13 and pimobendan were still active after 6.5 h. However, the cardiotonic effect of 13 was at least 2-fold that of pimobendan after this period of time. The structural requirements necessary for optimal cardiotonic activity within this novel class of indole derivatives are a heterocyclic aromatic ring in position 2, a hydrogen or a methyl group in position 3, and a dihydropyridazinone ring system in position 5 of the indole.

Animals↗
PubMed1996

Indole derivatives as a new class of steroid 5 alpha-reductase inhibitors.

A series of indole derivatives with varied substituents on the alpha, beta-unsaturated double bond were synthesized and evaluated for their ability to inhibit rat prostatic 5 alpha-reductase. Compounds possessing an ethyl substituent at the beta-position of the double bond showed potent inhibitory activity. Among them, (Z)-4-{2-[[3-[1-(4,4'-difluorobenzhydryl)indol-5-yl]-2-pentenoy l]- amino]phenoxy}butyric acid (16, KF20405) showed the maximum potency with an IC50 value of 0.48 +/- 0.086 nM, which was 20-fold higher potency than 1 (MK-906). Compound 16 effectively inhibited DHT production 4 h after a 3 mg/kg oral administration. Several potent indole derivatives, 1 and 2 ((+/-)-ONO-3805), were tested versus rat and human isozymes. Nonsteroidal inhibitors such as indole derivatives and 2 were 2-3 orders of magnitude less potent for human type 2 isozyme than steroidal inhibitor 1 and expressed a significant species deference for these isozymes.

5-alpha Reductase Inhibitors↗
PubMed2000

Neighboring group participation of the indole nucleus: An unusual DAST-mediated rearrangement reaction

A rearrangement reaction involving the indole nucleus was investigated using stereochemical markers and low-temperature NMR experiments. Treatment of (3S, 4S)-3-hydroxy-4-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (>90% ee) with diethylaminosulfur trifluoride gave stereospecifically (3S, 4S)-4-fluoro-3-(2-phenyl-1H-indol-3-yl)-piperidine-1-carboxylic acid benzyl ester (>90% ee) with complete regioselectivity. The initial formation of a reactive spirocyclopropyl-3H-indole intermediate is believed to be responsible for the stereo- and regiochemical outcome of the reaction.

Journal Article↗
PubMed2004

Indole synthesis by controlled carbolithiation of o-aminostyrenes.

An effective synthesis of the functionalized indole ring system has been developed from substituted o-aminostyrene starting material. Our methodology involves a novel cascade reaction sequence of alkyllithium addition to the styrene double bond and subsequent trapping of the intermediate organolithium with a suitable electrophile, followed by an in situ ring closure and dehydration to generate the indole ring. This new reaction sequence allows for the introduction of molecular diversity at all positions on the indole scaffold. The procedure was shown to be successful with a range of both C and N substituents on the o-aminostyrenes. The reaction sequence was tolerant to the reactivity range of alkyllithiums such as tert-, sec-, and n-butyllithium. The electrophiles used were DMF, which generated indole products with C-2 unsubstituted, and nitriles, which incorporated the nitrile substituent at C-2. The o-aminostyrene starting materials were generated by a Pd-catalyzed cross-coupling reaction of a vinyl boronic acid equivalent with the readily available substituted o-bromoanilines.

Journal Article↗
PubMed2006

Mechanism of triplet photosensitized Diels-Alder Reaction between indoles and cyclohexadienes: theoretical support for an adiabatic pathway.

Diels-Alder reactions between indoles (InHs) and 1,3-cyclohexadienes (CHDs) were achieved by using aromatic ketones as photosensitizers. For instance, irradiation of deaerated dichloromethane solutions containing benzoylthiophene (BT, 1 mM), indole (20 mM), and phellandrene (40 mM), in the presence of an acylating agent, led to the N-acetylated Diels-Alder cycloadduct in 46% yield (endo:exo ratio of 1.8:1). Energy transfer from the BT triplet to the CHD gave rise to diene dimers as byproducts. Several combinations of CHDs, InHs, and aromatic ketones were tested; the Diels-Alder reaction was found to be a general process, except when the indole nucleus was substituted at position 2 or 7 and when aromatization of the CHD was favored. Theoretical calculations support a stepwise mechanism involving a triplet ternary complex TC(T1), arising from a nearly barrierless reaction between CHD and the 3(BT...HIn) exciplex. All subsequent steps proceed downhill in the triplet excited state, leading to a triplet cycloadduct-sensitizer CA-BT(T1) radical pair. Attempts to detect this species, which is basically an aminyl/BT ketyl radical pair, were performed by laser excitation of a solution containing BT, phellandrene, and indole. The observed transient absorption spectra could be compatible with the added spectra of the expected components of the radical pair.

Journal Article↗
PubMed2005

Hydrogen bonding to pi-systems of indole and 1-methylindole: is there any OH...phenyl bond?

The weak hydrogen-bonded complexes between proton donors and the pi-cloud of indole and 1-methylindole (MI) are investigated theoretically by three different methods: DFT/B3LYP, MPW1B95, and MP2. This study addresses the question as to whether the 1:1 complex can only form between the proton and the pi-cloud of the pyrrole part of indole or if there also exists a 1:1 complex between the proton and the pi-cloud of the phenyl ring. For the water-indole system, the more elaborate MP2 and MPW1B95 methods yield only one minimum with a hydrogen bond to the pyrrole part and weak secondary interactions to the phenyl ring, in agreement with a recent criticism by Van Mourik (Chem. Phys. 2004, 304, 317-319) that the B3LYP functional is unable to account for the dispersion interaction. However, for the 1:1 complexes between MI and 2-propanol, all three methods indicate that both the five-membered and the six-membered rings of the indole chromophore can form pi-complexes. For the MI-trifluoroethanol (TFE) system, it is shown that the ethanol conformation is specific for the interaction site: for the complex to the five-membered ring, TFE is in the cis-gauche conformation, while for the complex to the six-membered ring site, it is in the trans conformation. These results are discussed as a function of local interactions in the systems.

Journal Article↗
PubMed2001

Solid-phase synthesis of 2,3,5-trisubstituted indoles.

2,3,5-Trisubstituted indoles are synthesized in three steps starting from resin-bound aniline 2. R1 is introduced by a palladium-mediated coupling of the aryl iodide with terminal alkynes followed by intramolecular cyclization to form the indole core. Acylation at C-3 with an acid chloride in the presence of AlCl(3) catalyst introduces R2. The indole C-5 position is then diversified either by Sonagashira or Suzuki couplings with the aryl bromide. Finally, indole N-1 can be modified by post-cleavage methylation. [reaction: see text]

Journal Article↗
PubMed2004

A general synthesis of substituted indoles from cyclic enol ethers and enol lactones.

[reaction: see text] X = CH2, C[double bond]O, R2 = H, alkyl. A general method was developed for the one-pot synthesis of highly functionalized indoles from simple, commercially available aryl hydrazines and cyclic enol ethers. Enol lactones were also used as substrates, affording substituted indole acetic acid or indole propionic acid derivatives. This procedure affords 2,3-disubstituted indoles as single regioisomers from the appropriately substituted enol ether or enol lactone. This method was highlighted in the efficient synthesis of the antimigraine drug sumitriptan and the antiinflammatory drug indomethacin.

Journal Article↗
PubMed2003

The quenching of indolic compounds by monosubstituted benzenes and the photoreaction with chlorobenzene.

The quenching of the excited singlet of indole and its methyl derivatives by monosubstituted benzenes has been studied in three solvents of different polarities and bimolecular quenching rate constants have been determined. Below the diffusion limit the rate constants decrease when solvent polarity increases, with the exception of those for the quenching by benzonitrile. For the latter the rate constants are near the diffusion limit in all cases. The decrease may be understood in terms of a lower energy of the indole excited state in the more polar solvents. In cyclohexane the remnant emission in the presence of high concentration of the quencher is clearly red shifted, indicating the presence of a new emitting species that can be ascribed to the presence of an exciplex. In some cases the emission of the exciplex can be clearly separated from the molecular fluorescence. In the quenching by chlorobenzene in ethyl acetate and acetonitrile a new highly fluorescent product is formed. This photoreaction is observed with all the indole derivatives and the kinetics of the reaction was followed by the increase in fluorescence intensity at a wavelength were the reactants do not emit. Three major products were identified as phenyl substituted indoles by GC-MS and their fluorescence emission and excitation spectra.

Journal Article↗
PubMed1995

Identification of a 23 kDa protein from maize photoaffinity-labelled with 5-azido-[7-3H]indol-3-ylacetic acid.

A 23 kDa protein (p23) was identified in microsomal extracts from maize coleoptiles by photoaffinity labelling with 5-azido-[7-3H]indol-3-ylacetic acid ([3H]N3IAA). Labelling of p23 was blocked by unlabelled IAA, N3IAA, indol-3-ylbutyric acid and indol-3-yl-lactate. In addition, labelling was efficiently decreased by tryptophan, as well as by the scavenger p-aminobenzoic acid. Labelling was, however, not affected by synthetic auxins such as 1-naphthylacetic acid or 2,4-dichlorophenoxyacetic acid. Competition data suggest that the label was probably bound via the indole ring, and hence labelling was not specific for auxins. The 23 kDa protein was solubilized from crude microsomes by extraction with Triton X-100 and purified to homogeneity by ion-exchange, size-exclusion and reversed-phase chromatography. After electroblotting, the amino acid sequences of the p23 N-terminus as well as the several tryptic peptides were obtained. Database comparisons revealed sequence identity with a maize manganese superoxide dismutase. We conclude that photoaffinity labelling of p23 was pseudo-affinity, and therefore the binding site for IAA is not specific.

4-Aminobenzoic Acid↗
PubMed1996

Long-term follow-up of indolent mastocytosis in adults.

OBJECTIVE: To evaluate the natural course of indolent mastocytosis in adults. DESIGN: A retrospective long-term follow-up study. SETTING: The Department of Endocrinology of a University Hospital. PATIENTS: Sixteen adult patients with a diagnosis of indolent mastocytosis and sufficient biochemical data for statistical analysis. One patient had paediatric-onset cutaneous mastocytosis, whilst the others had adult-onset systemic mastocytosis. Ages at the end of follow-up ranged from 23 to 79, median 50 years. Follow-up periods per patient lasted from 13 to 135 months, median 90 months. MEASUREMENTS: Urinary excretions of the histamine metabolites N tau-methylhistamine (MH) and N tau-methylimidazoleacetic acid (MIMA), and signs and symptoms of the disease. RESULTS: The excretion of MH but not MIMA increased in four patients (ages 37, 45, 61 and 65 years) and decreased in two patients (ages 26 and 48 years), including the only patient with paediatric-onset cutaneous mastocytosis. The excretion of MIMA but not MH increased in none and decreased in one patients (age 51 years). The excretions of both MH and MIMA increased in one patient (age 23 years) and decreased in two patients (ages 65 and 79 years). The excretion of MH and MIMA can be considered to have been stable in one patient (age 49 years). In the five remaining patients, observation periods were rather short. A definite judgement on the course of their disease could not be given. In the two patients in whom the excretion of both MH and MIMA decreased, the enlarged spleen decreased in size, whilst in the other patients, signs and symptoms did not change. There were no accompanying myeloproliferative disorders in any patient. No special treatment aiming at a reduction in mast cell load has been given. Rates of change over the whole follow-up period ranged from -8.4 to +25.1% per year. CONCLUSION: The natural course of indolent adult-onset mastocytosis is not always progressive. Our data show that the activity of adult-onset indolent mastocytosis, as measured by urinary excretion of MH and MIMA and clinical signs and symptoms, can substantially decline, especially in older patients.

Adult↗