2-Aryl indole NK1 receptor antagonists: optimisation of indole substitution

The synthesis and biological evaluation of a series of 2-aryl indoles with high affinity for the human neurokinin-1 (hNK1) receptor are reported, concentrating on optimisation of the indole substitution.     

Photoproduction of indole 3-acetic acid by Rhodobacter sphaeroides from indole and glycine

Rhodobacter sphaeroides photoproduced indole 3-acetic acid (IAA) when the precursor L-tryptophan was added to the basal medium. Of the other organic carbon sources that influenced IAA formation from L-tryptophan, -ketoglutaric acid gave the maximum formation of 530 mg 1^–1 in less than 24 h of illuminated anaerobic incubation. IAA was also produced from indole, glycine and glucose together by Rb. sphaeroides under photoanaerobic conditions yielding 61 mg l^–1 within 30 fh.     

Synthesis and biological activity of 8beta-substituted hydrocodone indole and hydromorphone indole derivatives.

The 8beta-unsubstituted and substituted analogues of hydrocodone indole and hydromorphone indole were synthesized and their binding affinities to opioid receptors were determined. Introduction of an 8beta-methyl group into the indolomorphinan nucleus increased affinity at all opioid receptors. 6,7-Dehydro-4,5alpha-epoxy-8beta-methyl-6,7,2',3'-indolomorphinan (9) was found to be a delta antagonist with subnanomolar affinity (0.7 nM) for the delta-opioid receptor, and to have good delta-selectivity (mu/delta=322).     

Biogenetic-type synthesis of the indole alkaloids

A review of the rationale and methodology for the laboratory construction of the major classes of indole alkaloid based on their known or presumed biosynthesis is presented. The experimental results obtained provide analogies for the principal condensation and rearrangement reactions uncovered in biochemical investigations in this field and suggest new incorporation experiments. The prediction and discovery of new classes of alkaloid based on the observed transformations have been made and, in turn, new theories have been developed to explain some of the hitherto unsolved problems of biotransformation and structure in this series.Finally, the suggestion is made that many of the complex structures encountered in the various families may arise through rather unspecific processes, some indeed of a nonenzymic nature.     

Anticancer indole alkaloids of Ervatamia heyneana

The wood and stem bark of Ervatamia heyneana (Apocynaceae) yielded 14 indole alkaloids and 3 triterpenoids. Six of these isolates, camptothecin (2), 9-methoxycamptothecin (3), coronaridine (1), pericalline (25), heyneatine (18) and 10-methoxyeglandine- N-oxide (4) displayed cytotoxic activity. Three of the indole alkaloids 18, 4 and 10-hydroxycoronaridine (8) are new members in the iboga series and their structures were determined by a combination of spectral interpretation and chemical correlation.     

A three-component Fischer indole synthesis

This protocol describes a three-component approach to multiply-substituted indoles from nitriles, organometallic reagents and arylhydrazine hydrochloride salts. The condensation of organolithium or Grignard reagents with nitriles produces metalloimines, which under acidic conditions and in the presence of arylhydrazines lead to arylhydrazones, the starting materials for the Fischer indole reaction. Combining this approach with the Fischer indole reaction produces indoles in an efficient, one-pot process. The procedure takes approximately 20 h to complete: 3 h for metalloimine formation, 15 h for the Fischer indole reaction and 2 h for isolation and purification.     

Combinatorial synthesis of libraries of indole derivatives

The synthesis of two indole derivative libraries is described. 2-Acyl-3-amino-indoles 4 can easily be accessed by treatment of the intermediates 3 with bases in a one-pot reaction sequence whereas the reaction of the isolated intermediates 5 (R(3)=aromatic-, heteroaromatic, or cycloalkyl) with acid chlorides yielded the novel indole derivatives 6. The products were purified by reversed phase column chromatography and obtained in multi-milligram quantities in acceptable yields.     

Synthesis and anti-inflammatory activity of indole glucosinolates

The nitronate and nitrovinyl methods to synthesize indole glucosinolates (GLs) have been investigated. The results were applied to generally the most prevalent natural indole glucosinolates to synthesize 4-methoxyglucobrassicin (MGB) and neo-glucobrassicin (NGB) in moderate overall yield for the first time. The anti-inflammatory activity of the synthetic indole GLs was determined by inhibition of TNF-α secretion in LPS-stimulated THP-1 cells. The data showed that glucobrassicin (GB) exhibited higher activity than other synthetic indolyl GLs.     

Excitation of indole analogs by phagocytosing leukocytes

The system suspended with phagocytosing leukocytes and related system produce weak light which could be greatly amplified by indole analogs with plain fatty acids at 3 position. Main emitting species in indole-3-acetic acid or indole-3-propionic acid-sensitized system was analyzed spectrometrically in the dark and ascribed to the transition of an excited indole compound in triplet state to its ground state. Such an excited species would be generated by the oxidative way of the indole analogs but not through the dioxetane structure of 2 and 3 positions on indole ring.     

Antiplasmodial activity of aspidosperma indole alkaloids.

The antiplasmodial activity of twelve alkaloids with an aspidospermane skeleton was estimated in vitro on chloroquine-resistant and sensitive strains of Plasmodium falciparum. Seven tetracyclic alkaloids possessing a free ethyl chain such aspidospermine, showed IC50 after incubation for 72 h between 3.2 and 15.4 microM. Moreover, four pentacyclic alkaloids with ethyl chain included in a tetrahydrofuran, such haplocine, showed a reduced activity, with IC50, after 72 h, between 22.6 and 52.6 microM. According to these results, a chloroquine-potentiating experiment was also performed with two of the most active compounds. Isobolograms were obtained and demonstrated a synergic effect of N-formyl-aspidospermidine and aspidospermine when associated with chloroquine. The cytotoxicity and the selectivity index of some alkaloids were also estimated.     

The use of 6-(difluoromethyl)indole to study the activation of indole by tryptophan synthase

6-(Difluoromethyl)indole has been characterized and developed as a probe for the turnover of indole by the bifunctional enzyme, tryptophan synthase (alpha 2 beta 2). The neutral form of the indolyl species undergoes a slow and spontaneous hydrolysis to produce 6-formylindole with a rate constant (k1) of 0.0089 +/- 0.0001 min-1. The overall rate is independent of pH in the range of 3.5-10.5. Above pH 10.5, the observed rate increases are due to the high reactivity of the anionic form of the indole; deprotonation at N-1 accelerates hydrolysis by 10(4)-fold (k2, 97 +/- 2 min-1). The magnitude of this effect provides a technique for detecting the formation or stabilization of the anionic form of indole. 6-(Difluoromethyl)indole is recognized and processed by the beta subunit of tryptophan synthase. Selective inactivation of the beta subunit prevents enzymatic processing of 6-(difluoromethyl)indole. Chromatographic isolation and mass spectral analysis has identified 6-(difluoromethyl)tryptophan as the sole turnover product of the indolyl substrate. The lack of enzyme-promoted dehalogenation does not exclude the formation of an indole anion during turnover but rather the data suggest that rapid carbon-carbon bond formation (greater than 5300 min-1) prevents the accumulation of this anion.     

Ring oxygenated indole glucosinolates of Brassica species

Detailed chemical, degradative and spectroscopic analysis of two ring oxygenated indole glucosinolates isolated from Brassica species has confirmed these to be substituted in the 4- rather than the 5-position, although the latter had been suggested on biosynthetic grounds.     

A gas-sensor-dip-electrode for on-line measurement of indole

Summary A gas-sensor-dip-electrode (GSDE) for continuous on-line measurement of indole in liquid was developed. The response time of the GSDE with a gas-sensor from SnO₂-type could be reduced to 20 seconds with a Cuprophan membrane (thickness, 37m). A linear range for the indole determination from 0 to 2 g l^–1 is possible and the sensor readings agreed well with simultaneous indole determination by HPLC.