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A method for the preparation of chromeno[3,4-b]pyrrol-4(3H)-ones via the synthesis of the corresponding 3-arylpyrrole-2-carboxylates from pseudonitrosites by the Barton–Zard reaction was developed. As a result of selective O-demethylation upon exposure to BBr3, the lactone ring closes with the formation of substituted chromeno[3,4-b]pyrrolones in moderate yields.

A series of 3,4-diarylpyrrole-2-carboxamides was synthesized using the Barton—Zard reaction of nitrostilbenes with ethyl isocyanoacetate in the key stage. The antiproliferative properties of these compounds were studied on a sea urchin embryo model, as well as on 60 human tumor cell lines.

The 1,3-dipolar cycloaddition reaction of isoquinolinium ylides to nitrostilbenes provides an approach to 1,2-diarylpyrrolo[2,1

1,3-Substituted pyrazolo[3,4-b]pyridinones 11-18 were synthesized by a three-component condensation of Meldrum's acid with aryl aldehydes and 1,3-substituted 5-aminopyrazoles. Their biological activity was evaluated using the in vivo phenotypic sea urchin embryo assay and the in vitro cytotoxicity screen against human cancer cell lines. In the sea urchin embryo model, 1-benzimidazolyl-pyrazolo[3,4-b]pyridinones 11 caused inhibition of hatching and spiculogenesis at sub-micromolar concentrations. These compounds also selectively and potently inhibited growth of the MOLT-4 leukemia cell line. Subsequent structure-activity relationship studies determined the benzimidazolyl fragment as an essential pharmacophore for both effects. We applied numerous techniques for target identification. A preliminary QSAR target identification search did not result in tangible leads. Attempts to prepare a relevant photoaffinity probe that retained potency in both assays were not successful. Compounds 11 were further characterized for their activity in a wild-type versus Notch-mutant leukemia cell lines, and in in vitro panels of kinases and matrix metalloproteinases. Using a series of diverse modulators of spiculogenesis as standards, we excluded multiple signaling networks including Notch, Wnt/β-catenin, receptor tyrosine kinases (VEGF/VEGFR, FGF/FGFR), PI3K, and Raf-MEK-ERK as possible targets of 11. On the other hand, matrix metalloproteinase-9/hatching enzyme was identified as one potential target.

Free-radical-scavenging capacity antioxidant and membrane-protective properties of natural and related synthetic allylpolyalkoxybenzenes with different numbers of alkoxy/methoxy groups in the aromatic ring were evaluated using several in vitro models. These included the DPPH assay, inhibition of lipid peroxidation products accumulation, inhibition of H2O2-induced hemolysis, and oxidation of oxyhemoglobin. A synthetic protocol for the synthesis of natural nothoapiol (9) from a parsley seed metabolite, apiol (7), was developed. A structure-activity relationship study revealed that both the methylenedioxy fragment and methoxy groups in the aromatic ring are favorable for antioxidant activity. Hydroxyapiol (14), containing a hydroxy group in the aromatic core, was identified as the most potent compound. The pentaalkoxy-substituted nothoapiol (9) showed antioxidant activity in mouse brain homogenates, whereas in mouse erythrocytes it exhibited a marked pro-oxidant effect. Despite their low free-radical-scavenging capacity, allylpolyalkoxybenzenes can contribute to the total antioxidant potencies of plant essential oils.

Barton-Zard reaction of nitrostilbenes with ethyl isocyanoacetate carried out in EtOH in the presence of K2CO3 allowed us to minimize the formation of side products and to obtain 3,4-diarylpyrrole-2-carboxylates in high yields.

A series of both novel and reported combretastatin analogues, including diarylpyrazoles, -isoxazoles, -1,2,3-triazoles, and -pyrroles, were synthesized via improved protocols to evaluate their antimitotic antitubulin activity using in vivo sea urchin embryo assay and a panel of human cancer cells. A systematic comparative structure-activity relationship studies of these compounds were conducted. Pyrazoles 1i and 1p, isoxazole 3a, and triazole 7b were found to be the most potent antimitotics across all tested compounds causing cleavage alteration of the sea urchin embryo at 1, 0.25, 1, and 0.5 nM, respectively. These agents exhibited comparable cytotoxicity against human cancer cells. Structure-activity relationship studies revealed that compounds substituted with 3,4,5-trimethoxyphenyl ring A and 4-methoxyphenyl ring B displayed the highest activity. 3-Hydroxy group in the ring B was essential for the antiproliferative activity in the diarylisoxazole series, whereas it was not required for potency of diarylpyrazoles. Isoxazoles 3 with 3,4,5-trimethoxy-substituted ring A and 3-hydroxy-4-methoxy-substituted ring B were more active than the respective pyrazoles 1. Of the azoles substituted with the same set of other aryl pharmacophores, diarylpyrazoles 1, 4,5-diarylisoxazoles 3, and 4,5-diaryl-1,2,3-triazoles 7 displayed similar strongest antimitotic antitubulin effect followed by 3,4-diarylisoxazoles 5, 1,5-diaryl-1,2,3-triazoles 8, and pyrroles 10 that showed the lowest activity. Introduction of the amino group into the heterocyclic core decreased the antimitotic antitubulin effect of pyrazoles, triazoles, and to a lesser degree of 4,5-diarylisoxazoles, whereas potency of the respective 3,4-diarylisoxazoles was increased.

Chlorination of 1-hydroxyindole-5,6-dicarbonitriles and 1-hydroxypyrrolo[3,4-f]indole-5,7(1H,6H)-diones with N-chlorosuccinimide afforded previously unknown 3,3-dichloro-3Hindole 1-oxides instead of the expected 3-chloro-1-hydroxyindoles. The latter, however, were prepared in good yields by treatment of the above 3,3-dichloro-3H-indole 1-oxides with piperidine in ethanol. Reduction of 3,3-dichloro-5,6-dicyano-3H-indole 1-oxides with Zn in AcOH yielded the corresponding 3-chloroindole-5,6-dicarbonitriles.

Reaction of arylglyoxal oximes ArCOCH=NOH (Ar = 4-MeOC6H4, Ph) with 5-arylfurazanopyrazines proceeds as vicarious nucleophilic substitution of hydrogen in pyrazine ring with the elimination of hyponitrous acid, affording 5-(aroylmethylidene)-6-aryl-4H-furazano[3,4-b]pyrazines. Structure of the product was confirmed by X-ray diffraction.

3-Aryl-4-methylpyrrole-2-carboxylates were prepared via the Barton–Zard reaction using pseudonitrosites as a source of the corresponding nitroalkenes. The starting pseudonitrosites were, in turn, obtained via addition of N2O3 to propenylbenzenes available from the natural plant essential oils.

1,3-Substituted pyrazolo[3,4

The C-3 acylation of 1-hydroxyindole derivatives with aliphatic acid anhydrides was accomplished in high yields using BF3·Et2O as a promoter, affording the corresponding 3-acyl-1-acyloxyindoles which in turn were readily hydrolyzed to the corresponding 3-acyl-1-hydroxyindole derivatives.

Alkoxy-substituted 1-aryl-3-(arylamino)prop-2-en-1-ones and 1-aryl-3-(arylamino)but-2en-1-ones were synthesized by the addition of anilines to 1,3-dioxo derivatives or aryl ethynyl ketones. The cis-trans isomerism of these compounds was studied. Biological tests on a sea urchin embryo model showed that 1-aryl-3-(arylamino)prop-2-en-1-ones exhibit an antimitotic effect both via microtubule destabilization and through the action on other cellular targets. The antiproliferative activity of these compounds increases with an increase in the number of alkoxy substituents in 1-aryl ring, whereas the presence of one methoxy group in the para position proved to be optimal for the arylamino moiety.

The Vilsmeier–Haack formylation of 4-(2-aryl-2-oxoethyl)-5-nitrophthalonitriles followed by reduction affords 3-acyl-1-hydroxy- 1H-indole-5,6-dicarbonitriles.

Simple chiral precursors for the preparation of methylene-expanded C-nucleosides were developed, using as key steps pyrolysis of cellulose to levoglucosenone followed by hydrogenation and introduction of vinyl and ethynyl fragments to the 2-position.

Levoglucosenone, an optically active α,β-unsaturated ketone available from cellulose, undergoes a stereoselective oxa-Michael-aldol domino reaction with 2-hydroxybenzaldehydes with the formation of optically active oxepino[4,5-b]chromen-1-ones. These compounds attacked by nucleophiles undergo recyclization to 4-substituted oxepino[3,4-b]chromen-11a-ols, while their oximes treated with SOCl2 are converted to 3-cyano-2H-chromenes through the Beckmann fragmentation.

The Vilsmeier–Haack formylation of 4-(2-aryl-2-oxoethyl)-5-nitrophthalonitriles followed by reduction affords 3-acyl-1-hydroxy- 1H-indole-5,6-dicarbonitriles.

Reactions of 4-bromo-5-nitrophthalonitrile (BNPN) with enolates of alkyl 4-R-2,4-dioxobutanoates gave alkyl 3-acyl-5,6-dicyanobenzofuran-2-carboxylates, 4-(2-R-2-oxoethyl)-5-nitrophthalonitriles, or 3-acyl-1,2-benzoxazole-5,6-dicarbonitriles. With a base, 4-(2-R-2-oxoethyl)-5-nitrophthalonitriles either undergo nitro-nitrite rearrangement resulting in 3-acyl-1,2-benzoxazole-5,6-dicarbonitriles or yield 2-R-benzofuran-5,6-dicarbonitriles with a nitro group displacement.

Chlorination of 2-aryl-1-hydroxyindole-5,6-dicarbonitriles with N-chlorosuccinimide affords previously unknown 3,3-dichloro-3H-indole 1-oxides instead of the expected 1-hydroxy- 3-chloroindoles. The latter can be prepared in good yields by treatment of the above 3,3-dichloro-3H-indole 1-oxides with piperidine in ethanol.

A novel peri -annulated heterocyclic system of 1,2-dihydrobenz[6,7]oxepino[4,3,2- cd ]indole was prepared starting from TNT via 4,6-dinitro-1-tosylindoline as a key intermediate. Base-induced C C bond shift in 1,2-dihydrobenz[6,7]oxepino[4,3,2- cd ]indoles affords isomeric 2,11-dihydrobenz[6,7]oxepino[4,3,2- cd ]indoles.

1,3-Dinitro[b,f]dibenzoxepine undergoes nucleophilic substitution with O-and S-nucleophiles, the nitro group at position 1 (peri-nitro group) being selectively replaced. The factors responsible for the selectivity of the reaction are discussed.

2,4,6-Trinitrotoluene readily reacts with 1-nitroso-2-naphthol to afford 9,11-dinitrobenzo[f]naphtho[2,1-b][1,4]oxazepine. The nitro groups of the latter undergo displacement by O- and S-nucleophiles with preferential substitution of the 11-NO2 (peri-nitro group). The structures of the substitution products are confirmed by X-ray diffraction and 1H NMR NOE experiments.

Levoglucosenone (a chiral α,β-unsaturated ketone derivative of cellulose) serves as a starting compound in 2 and 3 step syntheses of chiral cyclopropanecarboxylic acids and 3-oxabicyclo[3.1.0]hexane-2-ones, respectively.

5,7-Dinitroquinazoline-4-ones undergo nucleophilic displacement of a nitro group with N-, S-, and O-nucleophiles. In contrast to previously studied dinitro-substituted benzoannulated five- and seven-membered heterocycles (where a high degree of selectivity was observed), these quinazolines mostly yield mixtures of regioisomeric substitution products. At the same time, primary and secondary amines react selectively to afford 5-aminoquinazolones (peri-substitution). A similar effect is observed for some other polynitroaromatic compounds with adjacent nitro and carbonyl groups. This phenomenon is attributed to a stabilization of the intermediate peri-sigma-complex by intramolecular hydrogen bond N(+)-H...O double bond C.

1,3-Dinitro[b, f][1,4]dibenzoxazepin-11(10H)-one enters nucleophilic substitution reactions with N-nucleophiles, azide ion preferably replacing the nitro group in position 3, whereas amines the one in position 1. Structures of the substitution products were confirmed by X-ray diffraction and 1H NMR NOE spectroscopy. The selectivity observed in the reaction with amines was supposed to be caused by the stabilization of the intermediate σ-complex with the NH…O intramolecular hydrogen bond.

Levoglucosenone (a chiral α,β-unsaturated ketone derivative of cellulose) underwent stereoselective cyclopropanation with sulfonium ylides to form chiral trisubstituted cyclopropanes annulated with the carbohydrate moiety in high yields.

[Reaction: see text]. 1,3-dinitrodibenz[b,f][1,4]oxazepin-11(10H)-one, prepared by intramolecular displacement of nitro group in N-(2-hydroxyphenyl)-2,4,6-trinitrobenzamide, reacts with O- and S-nucleophiles to yield the products of mono- or bis-substitution of the nitro groups. The nitro group in position 3 is displaced first. This observation is in contrast with earlier results for the nitro-substituted benzoannulated five-membered heterocycles. This difference in reactivity is likely due to the increased steric hindrance for peri-nitro group displacement in the case of the benzoannulated seven-membered heterocycle. N-Alkylation of the nitro-substituted dibenz[b,f][1,4]oxazepin-11(10H)-ones yields analogues of a known antidepressant drug Sintamil. The structure of the products is confirmed by NOE experiments and alternative synthesis.

DL-arylalanines were synthesized from corresponding aromatic aldehydes by an efficient “one-pot” procedure involving Erlenmeyer reaction and subsequent reduction of the resulting oxazolones (without prior isolation) using P/HI.

Levoglucosenone, a chiral α,β-unsaturated ketone derived from cellulose, undergoes a stereoselective domino oxa-Michael–aldol reaction with 2-hydroxybenzaldehydes affording optically active pyrano[3,4-b]chromenes. The latter are further converted into 2H-chromenes via a Beckmann fragmentation reaction.

2,4-Dinitro- and 2,4,6-trinitrotoluenes react with phthalic anhydride in boiling N,N-dimethylaniline to give nitro group reduction products.

1-R-4,6-Dinitroindoles 4–6 (R = H, Me, Ts) could be obtained from 2-picrylethanol 1 (readily available from TNT) via selective reduction of ortho-nitro group by N2H4/FeCl3 and subsequent treatment with TsCl, to yield a key intermediate 3. This intermediate was converted to the above mentioned indoles.

Reactions of 1-R-2,4,6-trinitrobenenes (R = alkyl, protected aldehyde, aminocarbonyl, cyano groups, or isoxazole ring) with thiol salts were investigated. In most cases, these reactions gave a mixture of minor para and major ortho substitution products. Reactions of N,N-disubstituted 2,4,6-trinitrobenzamides with S-,O-, and N-nucleophiles afforded products of substitution of the p-nitro group exclusively. 1-Cyano-2,4,6-trinitrobenzene was found to be the most reactive and the least selective: all three nitro groups can be substituted using an excess of thiol salts. 2-R-4, 6-dinitrobenzamides showed no regioselectivity under similar conditions to yield 1:1 mixtures of para and ortho isomers.

Benzylidenecyanoacetamide reacted with dimethylsulfonium phenacylide to form 2-benzoyl-1-cyano-3-phenylcyclopropanecarboxamide and a product of its intramolecular cyclization,viz., a derivative of 3-azabicyclo[3.2.1]hexan-2-one. The structures of the products were established by X-ray diffraction analysis.

N-Acetonylazoles react with chalcones in the presence of a base to givetrans-3,5-disubstituted 6-(N-azolyl)cyclohex-2-enones. Usually, the reactions are fast and high-yielding.

The reactions of stabilized sulfonium ylides with arylmethylenecyanothioacetamides proceed stereoselectively to yield 2-amino-4,5-dihydrothiophenes and cyclopropane-thiocarboxamides. The structures of the latter compounds were confirmed by X-ray diffraction analysis.

A series of 1,5-diaryl- and 4,5-diaryl-1,2,3-triazole derivatives of combretastatin A4 were synthesized and evaluated as antimitotic microtubule destabilizing agents using the sea urchin embryo model. Structure–activity relationship studies identified compounds substituted with 3,4,5-trimethoxyphenyl and 3,4-methylenedioxy-5-methoxyphenyl ring A and 4-methoxyphenyl ring B as potent antiproliferative agents with high cytotoxicity against a panel of human cancer cell lines including multi-drug resistant cells. 4,5-Diaryl-1,2,3-triazoles (C–C geometry) were found to be considerably more active than the respective 1,5-diaryl-1,2,3-triazoles (N–C geometry). Compound 10ad′ induced G2/M cell cycle arrest and apoptosis in human T-leukemia Jurkat cells via caspase 2/3/9 activation and downregulation of the antiapoptotic protein XIAP. A mitotic catastrophe has been evaluated as another possible cell death mode.

Previously unknown 5-azolylpyrans were obtained by reactions ofN-acetonyl- andN-phenacylimidazoles, -triazoles, and -tetrazoles with arylmethylenemalononitriles. The structure of 2-amino-3-cyano-6-methyl-5-(5-nitrotetrazol-2-yl)-4-phenyl-4H-pyran was established by X-ray structural analysis.

The reactions of levoglucosenone with urea, thiourea andN-cyano- andN-nitroguanidines result in pyrimidine systems fused with a carbohydrate fragment. In all cases, the cyclization occurs stereospecifically. The structures of different products of conversion of levoglucosenone were established on the basis of NMR and X-ray diffraction data.

Regioselective Michael addition of nitro and heterocyclic compounds to levoglucosenone, 1, is effectively catalyzed by amines and also by cathodic electrolysis. In comparison to the base-catalyzed reaction, it was found that under electrochemical conditions the reaction proceeds under milder conditions and with higher yields. Cathodically-initiated Michael addition of thiols to levoglucosenone using small currents produces the previously unknown threo addition product in several instances. The normal erythro isomer, identified as the kinetic product, tends to be formed when large currents are used. In contrast, slow, low current electrolyses promote equilibration of the two forms so that erythro can be converted to threo by the retro reaction and readdition. Addition of 2-naphthalenethiol to (R)-(+)-apoverbenone is also reported.

Regioselective Michael addition of nitro compounds to levoglucosenone (LG) is effectively catalyzed by cathodic electrolysis under mild conditions.

Carbanions formed from malononitrile and ethyl cyanoacetate have been found to react with pyridinium salts via ring-opening to form 1,1,7,7-tetrasubstituted hepta-1,3,5-trienes.