Study of 1-deoxy-1-(indol-3-yl)-L-sorbose, 1-deoxy-1-(indol-3-yl)-L-tagatose,and their analogs

Alkaline degradation of the ascorbigen 2-C-[(indol-3-yl)methyl]-alpha-L-xylo-hex-3-ulofuranosono-1,4-lactone (1a) led to a mixture of 1-deoxy-1-(indol-3-yl)-L-sorbose (2a) and 1-deoxy-1-(indol-3-yl)-L-tagatose (3a). The mixture of diastereomeric ketoses underwent acetylation and pyranose ring opening under the action of acetic anhydride in pyridine in the presence of 4-dimethylaminopyridine (DMAP) with the formation of a mixture of (E)-2,3,4,5,6-penta-O-acetyl-1-deoxy-1-(indol-3-yl)-L-xylo-hex-1-enitol (4a) and (E)-2,3,4,5,6-penta-O-acetyl-1-deoxy-1-(indol-3-yl)-L-lyxo-hex-1-enitol (5a), which were separated chromatographically. Deacetylation of 4a or 5a afforded cyclised tetrols, tosylation of which in admixture resulted in 1-deoxy-1-(indol-3-yl)-3,5-di-O-tosyl-alpha-L-sorbopyranose (12a) and 1-deoxy-1-(indol-3-yl)-4,5-di-O-tosyl-alpha-L-tagatopyranose (13a). Under alkaline conditions 13a readily formed 2-hydroxy-4-hydroxymethyl-3-(indol-3-yl)cyclopenten-2-one (15a) in 90% yield. Similar transformations were performed for N-methyl- and N-methoxyindole derivatives.     

The formation of 2-hydroxy-4-hydroxymethyl-3-(indol-3-yl)-cyclopent-2-enone derivatives from ascorbigens

A facile preparation is described of 3-(indol-3-yl)-2-hydroxy-4-hydroxymethylcyclopent-2-enone and its N-derivatives in 15-40% yields by the degradation of ascorbigen or its N-derivatives in a warm solution of L-ascorbic acid through a sequential domino reaction. The same cyclopentenone derivatives were obtained in 30-40% yields by the condensation of (N-alkylindol-3-yl)glycolic acids with ascorbic acid. 2,6-Dihydroxy-1-(indol-3-yl)hexa-1,4-diene-3-one and 2-hydroxy-4-hydroxymethyl-5-(indol-3-yl)cyclopent-2-enone were identified as intermediates in this reaction.     

Reaction of glycosyl isothiocynates with 3-indolylaminomethyl-ketone hydrochloride

Reaction of glycosyl isothiocyanate la-c with 3-indolylaminomethylketone hydrochloride(2) yielded glycosylthiourea derivatives 3a-c. Cyclodehydration of 3a-c with acetic anhydride afforded 5-(indol-3-yl)-2-[N-per-O-acetyl-D-glycopyranosyl)amino]thiazoles 4a-c. Deacetylation of 4a-c gave 5-(indol-3-yl)-2-[N-(D-glycopyranosyl) amino] thiazoles 5a-c.     

The development of potent and selective bisarylmaleimide GSK3 inhibitors

Many 3-aryl-4-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100 nM IC(50)), although few show significant selectivity (>100x) versus CDK2, CDK4, or PKCbetaII. However, combining 3-(imidazo[1,2-a]pyridin-3-yl), 3-(pyrazolo[1,5-a]pyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro[1,4]diazepino[6,7,1-hi]indol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (160 to >10,000-fold selectivity versus CDK2/4 and PKCbetaII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).     

Synthesis and cytotoxic activity of novel 1-((indol-3-yl)methyl)–1H-imidazolium salts

A series of novel 1-((indol-3-yl)methyl)–1H-imidazolium salts were prepared and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the 5,6-dimethyl-benzimidazole ring, and substitution of the imidazolyl-3-position with a naphthylacyl or 4-bromophenacyl group, were vital for modulating inhibitory activity of cell growth. In particular, 1-((N-Boc-indol-3-yl)methyl)-3-(2-naphthylacyl)-1H-5,6-dimethyl-benzimidazolium bromide was found to be the most potent derivative and more selective against myeloid liver carcinoma (SMMC-7721), lung carcinoma (A549) and breast carcinoma (MCF-7), with IC₅₀ values 1.9-fold, 1.7-fold and 4.8-fold lower than DDP. This compound can induce significant cell apoptosis in SMMC-7721 cells.     

REACTION Of GLYCOSYL ISOTHIOCYNATES WITH 3-INDOLYLAMINOMETHYL-KETONE HYDROCHLORIDE

ABSTRACT

Reaction of glycosyl isothiocyanate 1a-c with 3-indolylaminomethyl-ketone hydrochloride(2) yielded glycosylthiourea derivatives 3a-c. Cyclodehydration of 3a-c with acetic anhydride afforded 5-(indol-3-yl)-2-[N-per-O-acetyl-D-glycopyranosyl)amino]thiazoles 4a-c. Deacetylation of 4a-c gave 5-(indol-3-yl)-2-[N-(D-glycopyranosyl) amino]thiazoles 5a-c.     

Synthesis of new iso-C-nucleoside analogues from 2-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)ethanal

Treatment of 2-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)ethanal with malononitrile, cyanoacetamide and 2-cyano-N-(4-methoxyphenyl)acetamide, respectively, in the presence of aluminium oxide yielded 2-cyano-4-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)crotonic acid derivatives. Cyclization with sulfur and triethylamine was performed to synthesize the 2-amino-5-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)thiophene-3-carbonic acid derivatives, which were treated with triethyl orthoformate/ammonia and triethyl orthoformate, respectively, to furnish 6-(methyl 2-O-benzyl-4,6-O-benzylidene-3-deoxy-alpha-D-altropyranosid-3-yl)thieno[2.3-d]pyrimidine derivatives. Deprotection in two steps afforded 2-amino-5-(1,6-anhydro-3-deoxy-beta-D-altropyranos-3-yl)thiophene-3-carbonitrile and 6-(1,6-anhydro-3-deoxy-beta-D-altropyranos-3-yl)thieno[2.3-d]pyrimidine derivatives, respectively.     

A concise,total synthesis and antibacterial evaluation of 2-hydroxy-1-(1H-indol-3-yl)-4-methylpentan-3-one

Treatment of racemic 2-hydroxy-3-(1H-indol-3yl)propionic acid methyl ester (5) with isopropyl magnesium chloride provided the title compound 1 and its isomer, 3-hydroxy-1-(indol-3-yl)-4-methylpentan-2-one (9). Both enantiomers (>96% ee) of each component were obtained via semi-preparative chiral supercritical fluid chromatography (SFC). In contrast to previous reports, these compounds, as well as their acetate derivatives, were not active or very weakly active against 16 bacterial strains, including Escherichia coli, Bacillus subtilis and Staphylococcus aureus.     

Synthesis and cytotoxic potency of novel tris(1-alkylindol-3-yl)methylium salts: Role of N-alkyl substituents

Novel derivatives of tris(indol-3-yl)methane and tris(indol-3-yl)methylium salts with the alkyl substituents at the N-atoms of the indole rings were synthesized. An easy substitution of indole rings in trisindolylmethanes for other indoles under the action of acids is demonstrated, and the mechanism of substitution is discussed. To obtain trisindolylmethylium salts, the environmentally safe method of oxidation of trisindolylmethanes with air oxygen in acidic conditions was developed. Tris(1-alkylindol-3-yl)methanes and tris(1-alkylindol-3-yl)methylium salts represent three-bladed molecular propellers whose physico-chemical and biological properties strongly depend on the N-alkyl substituent. The cytotoxicity of novel compounds increased with the number of C atoms in the alkyl chains, with optimal number n = 3–5 whereas the derivatives with longer side chains were less cytotoxic. The most potent novel compounds killed human tumor cells at nanomolar-to-submicromolar concentrations, being one order of magnitude more potent than the prototype antibiotic turbomycin A [tris(indol-3-yl)methylium salt]. Apoptosis in HCT116 colon carcinoma cell line induced by tris(1-pentyl-1H-indol-3-yl)methylium methanesulfonate was detectable at concentrations tolerable by normal blood lymphocytes. Thus, N-alkyl substituted tris(1-alkylindol-3-yl)methylium salts emerge as perspective anticancer drug candidates.     

Bioreductively-activated prodrugs for targeting hypoxic tissues: elimination of aspirin from 2-nitroimidazole derivatives.

2-Nitroimidazoles were synthesised substituted with aspirin or salicylic acid, as leaving groups linked through the (imidazol-5-yl)methyl position. Activation of aqueous solutions by CO2*- (a model one-electron reductant) resulted in release of aspirin or salicylate, probably via the 2-hydroxyaminoimidazole. The analogous 2-nitroimidazole with bromide as leaving group eliminated bromide in < 1 ms via the radical-anion.     

Binding of N-acetylgalactosamine-specific lectins to spin-labeled galactosamine derivatives

Legume seed lectins specific for N-acetyl-alpha-D-galactosaminyl end groups from Amphicarpaea bracteata, lima bean, Griffonia simplicifolia, Dolichos biflorus, and soybean were compared with respect to binding of several spin-labeled derivatives of D-galactosamine by electron spin resonance and precipitin inhibition analysis. Spin-label II [methyl 2-[[(2,2,5,5-tetramethyl-1-oxopyrrolidin-3-yl) carbonyl]amino]-2-deoxy-alpha-D-galactopyranoside], spin-label III [1-(methyl 2-deoxy-alpha-D-galactopyranosid-2-yl)-3-(2,2,6, 6-tetramethyl-1-oxypiperidin-4-yl)-2-thiourea], and spin-label IV [1-[4-[[(methyl 2-deoxy-alpha-D-galactopyranosid-2-yl)amino]carbonyl]phenyl]-3-(2, 2,6-tetramethyl-1-oxypiperidin-4-yl)-2-thiourea] contain 2-N-(oxypiperidinyl) or 2-N-(oxypyrrolidinyl) substituents varying in length and polarity of the linker arm between the glycoside and nitroxide ring. Spin-labels II and III were found to bind very weakly to all the lectins tested (Kd greater than or equal to 1.0 mM). Spin-label IV, containing a planar, nonpolar 2-N-phenyl group, was bound very strongly (Kd = 0.1-0.4 mM) and was moderately immobilized (2T parallel = 48-56 G) by all lectins except that from D. biflorus. Notably, the affinity of spin-label IV to lima bean lectin was 18-fold greater than that for methyl N-acetyl-alpha-galactosaminide. These results suggest that when the bulky oxypiperidinyl moiety lies in a position close to the sugar ring, it interferes with binding; in the cases where a phenyl group spacer exists, the aromatic ring in some cases actually enhances binding.(ABSTRACT TRUNCATED AT 250 WORDS)     

Indole-3-acetic acid and 2-(indol-3-ylmethyl)indol-3-yl acetic acid in the thermophilic archaebacterium Sulfolobus acidocaldarius.

Indole-3-acetic acid (IAA) and 2-(indol-3-ylmethyl)indol-3-yl acetic acid were identified in lipid extracts of Sulfolobus acidocaldarius; they occurred at concentrations of 0.57 and 0.59 mumol/g (dry weight), respectively. The amount of IAA found in these cells is more than a thousand times greater than that found in a typical extract of a plant in which IAA serves as a plant growth hormone. Neither of these compounds was detected in the other archaebacteria that were analyzed; these included Sulfolobus sulfataricus, Halobacterium salinarium, and several strains of methanogenic bacteria. This is the first report of the natural occurrence of 2-(indol-3-ylmethyl)indol-3-yl acetic acid.     

Modulation of carrier-mediated uptake of abscisic acid by methyl jasmonate in Phaseolus coccineus L

The effects of methyl jasmonate and jasmonic acid on uptake of abscisic acid (ABA) by suspension-cultured runner-bean cells and subapical runner-bean root segments have been investigated. Increasing concentrations of methyl jasmonate inhibit ABA uptake by the cultured cells with a K _i of 22±3 M. This is not due to cytoplasmic acidification or to effects on metabolism of ABA, and is not additive with inhibition of radioactive ABA uptake by nonradioactive ABA. Uptake of indol-3-yl acetic acid (IAA) is unaffected by methyl jasmonate. The maximum effect of nonradioactive ABA in inhibiting uptake of radioactive ABA, previously shown to reflect saturation of an ABA carrier, is generally greater than the effect of maximally inhibitory concentrations of methyl jasmonate. Similar results were obtained with root segments, but longer incubation times were necessary to observe inhibitory effects of methyl jasmonate. Demethylation of methyl jasmonate to jasmonic acid does not appear to be required since similar concentrations of jasmonic acid had no observable direct effect on ABA uptake other than that attributable to cytoplasmic acidification. Histidine reagents, a proton ionophore and acidic external pH all affect in parallel the inhibition by methyl jasmonate and nonradioactive ABA of uptake of radioactive ABA by the cultured cells. There is no effect of ABA or nonradioactive methyl jasmonate on uptake of radioactive methyl jasmonate by the cultured cells. It is proposed that methyl jasmonate interacts with the ABA carrier. Various models for this interaction are discussed.Abbreviations ABA abscisic acid - DMO 5,5-dimethyloxazolidine-2,4-dione - IAA indol-3-yl acetic acid     

Chemiluminescence of bicyclic dioxetanes bearing a hydroxyphenyl moiety substituted with carbazolyl, indolyl or benzotriazolyl group in the coordination sphere.

Bicyclic dioxetanes bearing a 3-(carbazol-9-yl)-5-hydroxyphenyl 2a, 3-hydroxy-5-(indol-1-yl)phenyl 2b, or 3-(benzotriazol-1-yl)-5-hydroxyphenyl group 2c were synthesized. Base-induced decomposition of dioxetane 2a displayed intense light, the maximum wavelength (lambda(max) (CTICL)) of which changed depending on the crown ether complex of potassium t-butoxide used as a base, although the magnitude of lambda(max) (CTICL) change was considerably smaller than the case of dioxetane bearing a 3-(anthracen-9-yl)-5-hydroxyphenyl group 1. Chemiluminescence (CL) from 2b resembled closely that from 2a in response to the crown ether complexes. On the other hand, dioxetane 2c exhibited emission of red light on treatment with tetrabutylammonium fluoride. The colour of light changed significantly and exhibited two peaks in the CL spectrum when treated with complex of bulky dibenzyldiazacrown ether 13.     

N-(sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines: potent antagonists of human neuropeptide Y Y5 receptor

[3a,4,5,9b-Tetrahydro-1H-benzo[e]indol-2-yl]amines were prepared via reductive amination and concomitant cyclization of alpha-cyanomethyl-beta-aminotetralins. N-acylation with omega-sulfonamido-carboxylic acids and subsequent reduction afforded a series of N-(sulfonamido)alkyl[tetrahydro-1H-benzo[e]indol-2-yl]amines, which bound to the human neuropeptide Y Y5 receptor with nanomolar affinity.     

Development of indolequinone mechanism-based inhibitors of NAD(P)H:quinone oxidoreductase 1 (NQO1): NQO1 inhibition and growth inhibitory activity in human pancreatic MIA PaCa-2 cancer cells

NAD(P)H:quinone oxidoreductase 1 (NQO1) is currently an emerging target in pancreatic cancer. In this report, we describe a series of indolequinones, based on 5-methoxy-1,2-dimethyl-3-[(4-nitrophenoxy)methyl]indole-4,7-dione (ES936), and evaluate NQO1 inhibition and growth inhibitory activity in the human pancreatic MIA PaCa-2 tumor cell line. The indolequinones with 4-nitrophenoxy, 4-pyridinyloxy, and acetoxy substituents at the (indol-3-yl)methyl position were NADH-dependent inhibitors of recombinant human NQO1, indicative of mechanism-based inhibition. However, those with hydroxy and phenoxy substituents were poor inhibitors of NQO1 enzyme activity, due to attenuated elimination of the leaving group. The ability of this series of indolequinones to inhibit recombinant human NQO1 correlated with NQO1 inhibition in MIA PaCa-2 cells. The examination of indolequinone interactions in complex with NQO1 from computational-based molecular docking simulations supported the observed biochemical data with respect to NQO1 inhibition. The design of both NQO1-inhibitory and noninhibitory indolequinone analogues allowed us to test the hypothesis that NQO1 inhibition was required for growth inhibitory activity in MIA PaCa-2 cells. ES936 and its 6-methoxy analogue were potent inhibitors of NQO1 activity and cell proliferation; however, the 4-pyridinyloxy and acetoxy compounds were also potent inhibitors of NQO1 activity but relatively poor inhibitors of cell proliferation. In addition, the phenoxy compounds, which were not inhibitors of NQO1 enzymatic activity, demonstrated potent growth inhibition. These data demonstrate that NQO1 inhibitory activity can be dissociated from growth inhibitory activity and suggest additional or alternative targets to NQO1 that are responsible for the growth inhibitory activity of this series of indolequinones in human pancreatic cancer.     

Stereospecific synthesis of α-methylated amino acids

Summary. Both 2,5-trans and 2,5-cis disubstituted 2-tert-butyl-5-(indol-3-yl)methylimidazolidin-4-ones were synthesised and their enolates were prepared using LDA. While the enolate of the 2,5-trans disubstituted derivative could not be methylated, the enolate of the cis-2,5-disubstituted derivative was successfully methylated with methyl iodide to a product which on hydrolysis gave enantiomerically pure α-methyl-L-tryptophan. Received October 31, 1998, Accepted July 23, 1999     

Microwave assisted synthesis of new indophenazine 1,3,5-trisubstruted pyrazoline derivatives of benzofuran and their antimicrobial activity

2-[1-(5,8-Dihydro quinoxalino[2,3-b]indoloacetyl)-3-(1-benzofuran-2-yl)-4,5-dihydro-1H-pyrazol-5-yl] phenyl derivatives were synthesized from 2-(5,8-dihydro quinoxalino[2,3-b]indol-5-yl) acetohydrazide and (2E)-1-(1-benzofuran-2-yl)-4-phenylbut-2-en-1-ones derivatives using microwave-assisted route. The structures of all the compounds have been established on the basis of analytical and spectral data. Among the 14 compounds IPB-1, IPB-5, IPB-10, IPB-11 and IPB-12 were found good antibacterial activity and MICs were found bellow 10 μg/mL against Escherichia coli, Pseudomonas aeruginosa and Streptococcus aureus, which can compared with sparfloxacin and norfloxacin.     

Retinoic acid metabolism inhibition by 3-azolylmethyl-1H-indoles and 2, 3 or 5-(alpha-azolylbenzyl)-1H-indoles

Among a library of 70 azoles, 8 indole derivatives substituted in the 2-, 3- or 5- position with an azolylmethyl or alpha-azolylbenzyl chain were evaluated for retinoic acid (RA) metabolism inhibitory activity. The most active inhibitors identified in this study were 5-bromo-1-ethyl-3-methyl-2-[(phenyl)(1H-1,2,4-triazol-1-yl)methyl]-1H-indole (3) (68.9% inhibition) and 5-bromo-1-ethyl-2-[(4-fluorophenyl) (1H-1,2,4-triazol-1-yl)methyl]-3-methyl-1H-indole (6) (60.4% inhibition). At the same concentration (100 microM) ketoconazole exerted similar inhibitory effect (70% inhibition).     

Liquid chromatographic assay for the simultaneous determination of indole-3-carbinol and its acid condensation products in plasma

A high-performance liquid chromatographic method was developed for the simultaneous determination of indole-3-carbinol (I3C), 3,3'-diindolylmethane (DIM), [2-(indol-3-ylmethyl)-indol-3-yl]indol-3-ylmethane (LTr(1)), and indolo[3,2b]carbazole (ICZ). Compounds were extracted from mouse plasma using tert.-butyl methyl ether, incorporating 4-methoxy-indole as internal standard. Chromatographic separation utilized a Waters Symmetry RP18 in tandem with a Thermoquest BDS C(18) column, an acetonitrile-water gradient and UV (280 nm) in series with fluorescence (ex. 335 nm; em. 415 nm) detection. Calibration curves were linear (r(2)>0.99) between 50 and 15,000 ng/ml for I3C; 150 and 15,000 ng/ml for LTr(1); and 0.15 and 37.5 ng/ml for ICZ and the method was reproducible and precise (within-day and between-day coefficients of variation below 9.7 and 13%, respectively). The method described is suitable for comprehensive pharmacokinetic studies with indole-3-carbinol.