2-(3-Indolyl)acetamides and their oxazoline analogues: Anticancer SAR study.

We previously studied 2-aryl-2-(3-indolyl)acetohydroxamates as potential agents against melanoma. These compounds were ineffective in a mouse melanoma xenograft model, most likely due to unfavorable metabolic properties, specifically due to glucuronidation of the N-hydroxyl of the hydoxamic moiety. In the present work, we prepared a series of analogues, 2-aryl-2-(3-indolyl)acetamides and their oxazoline derivatives, which do not contain the N-hydroxyl group. We investigated the structure-activity relationship in both series of compounds and found that the 2-naphthyl is a preferred group at C-2 of the indole in the amide series, whereas the tetralin moiety is favorable in the same location in the oxazoline series. Overall, three compounds in the amide series have GI50 values as low as 0.2-0.3 µM and the results clearly indicate that the N-hydroxyl group is not necessary for high potency in vitro.

Synthesis of ß-Carbolines with Electrocyclic Cyclization of 3-Nitrovinylindoles.

The ß-carboline motif is common in drug discovery and among numerous biologically active natural products. However, its synthetic preparation relies on multistep sequences and heavily depends on the type of substitution required in the core of the desired ß-carboline target. Herein, we demonstrate that this structural motif can be accessed with the microwave-assisted electrocyclic cyclization of heterotrienic aci (alkylideneazinic acid) forms of 3-nitrovinylindoles. The reaction can start with 3-nitrovinylindoles themselves under two sets of conditions. The first one involves microwave irradiation of butanolic solutions of 3-nitrovinylindoles, whereas the second one consists of prior Boc protection of indolic nitrogen, where the protecting group cleanly comes off during the course of the reaction. Alternatively, the reaction can start with 3-nitrovinylindoles prepared in situ using various processes. Finally, the reaction may utilize indoles with ß-nitrostyrenes, likely involving the intermediacy of spirocyclic oxazolines, which rearrange to similar heterotrienic systems undergoing cyclization to ß-carbolines. As part of this study, several natural products, namely, alkaloids norharmane, harmane, and eudistomin N, were synthesized.

A New, Convenient Way to Fully Substituted α,ß-Unsaturated γ-Hydroxy Butyrolactams.

The synthesis of novel, highly functionalized 5-hydroxy 3-pyrrolin-2-ones via a two-step procedure involving an addition reaction between KCN and corresponding chalcones, followed by ring condensation of the obtained ß-cyano ketones with het(aryl)aldehydes under basic conditions is described. This protocol enables the preparation of various 3,5-di-aryl/heteroaryl-4-benzyl substituted α,ß-unsaturated γ-hydroxy butyrolactams, which are subjects of significant interest to synthetic organic and medicinal chemistry.

A Two-Step Synthesis of Unprotected 3-Aminoindoles via Post Functionalization with Nitrostyrene.

A novel, low-cost method for the preparation of not easily accessible free 3-aminoindoles has been developed. This approach is based on a well-established reaction between indoles and nitrostyrene in the presence of phosphorous acid, which results in the formation of 4'-phenyl-4'H-spiro[indole-3,5'-isoxazoles]. The latter could be transformed to corresponding aminated indoles by reaction with hydrazine hydrate in good or excellent yields upon microwave-assisted heating.

One-Pot Synthesis of Polynuclear Indole Derivatives by Friedel-Crafts Alkylation of γ-Hydroxybutyrolactams.

The Friedel-Crafts reaction of novel 3,5-diarylsubstituted 5-hydroxy-1,5-dihydro-2H-pyrrol-2-ones was used for low cost, one-pot preparation of polycyclic indole derivatives structurally similar to Ergot alkaloids.

A Diastereoselective Assembly of Tetralone Derivatives via a Tandem Michael Reaction and ipso-Substitution of the Nitro Group.

A highly diastereoselective tandem reaction of 2'-nitrochalcones is reported, involving Michael addition and a subsequent ipso-substitution of the nitro group to produce 1-tetralones with two contiguous chiral centers. A related annulation reaction of 2'-nitrochalcones with potassium cyanide affording 1-indanones with a C3-quaternary chiral center is also demonstrated.

Synthesis of 2-carboxyaniline-substituted maleimides from 2'-nitrochalcones.

A practical, one-pot approach to 3-anilino-4-(het)arylmaleimides by simple heating of aqueous DMSO solution of 2'-nitrochalcones with potassium cyanide in the presence of formic acid has been developed. This new reaction provides effective access to a variety of ß-substituted α-aminomaleimides which have recently become a subject of growing interest as small, easily modified and environmentally responsive fluorescent probes.

An Effective Synthesis of Previously Unknown 7-Aryl Substituted Paullones.

A straightforward three-step procedure affording a wide range of novel 7-aryl substituted paullone derivatives was developed. This scaffold is structurally similar to 2-(1H-indol-3-yl)acetamides-promising antitumor agents-hence, could be useful for the development of a new class of anticancer drugs.

A Convenient Way to Quinoxaline Derivatives through the Reaction of 2-(3-Oxoindolin-2-yl)-2-phenylacetonitriles with Benzene-1,2-diamines.

Microwave-assisted reaction between 2-(3-oxoindolin-2-yl)-2-phenylacetonitriles andbenzene-1,2-diamines leads to the high-yielding formation of the corresponding quinoxalines as sole, easily isolaable products. The featured transformation involves unusual extrusion of phenylacetonitrile molecule and could be performed in a short sequence starting from commonly available indoles and nitroolefins.

Reductive Cleavage of 4'H-Spiro[indole-3,5'-isoxazoles] En Route to 2-(1H-Indol-3-yl)acetamides with Anticancer Activities.

Unusual cascade transformation involving ring opening and 1,2-alkyl shift was observed upon the reduction of 4'H-spiro[indole-3,5'-isoxazoles] or 2-(3-oxoindolin-2-yl)acetonitriles with sodium borohydride. This reaction allowed for expeditious and highly efficient preparation of 2-(1H-Indol-3-yl)acetamides with antiproliferative properties.

Nitrovinylindoles as Heterotrienes: Electrocyclic Cyclization En Route to ß-Carbolines: Total Synthesis of Alkaloids Norharmane, Harmane, and Eudistomin N.

Unusual cascade transformation was developed involving microwave assisted electrocyclic cyclization of aci (alkylideneazinic acid) forms of nitrovinylindoles acting as heterotrienes. Subsequent one-pot reduction allowed for efficient access to ß-carbolines, including several natural products, alkaloids norharmane, harmane and eudistomin N.

One-Pot Synthesis of (E)-2-(3-Oxoindolin-2-ylidene)-2-arylacetonitriles.

A highly efficient and expeditious one-pot approach towards 2-(3-oxoindolin-2-yl)acetonitriles was designed, which involves a base-assisted aldol reaction of ortho-nitroacetophenones, followed by hydrocyanation, triggering an unusual reductive cyclization reaction.

Oxidative Cyclization of 4-(2-Aminophenyl)-4-oxo-2-phenylbutanenitriles into 2-(3-Oxoindolin-2-ylidene)acetonitriles.

A facile and highly efficient method for the preparation of 2-(3-oxoindolin-2-ylidene)acetonitriles from 4-(2-aminophenyl)-4-oxo-2-phenylbutanenitriles is described. The featured transformation operates via nucleophilic intramolecular cyclization and involves oxidation of the aniline moiety. Overall, this modification allowed for the improvement of yields and expansion of the reaction scope.

Improved Method for Preparation of 3-(1H-Indol-3-yl)benzofuran-2(3H)-ones.

3-(1H-Indol-3-yl)benzofuran-2(3H)-ones were efficiently accessed via polyphosphoric acid-mediated condensation of 3-(2-nitrovinyl)-1H-indoles with phenols.

Synthetic Studies toward 1,2,3,3a,4,8b-Hexahydropyrrolo[3,2-b]indole Core. Unusual Fragmentation with 1,2-Aryl Shift.

Base-assisted transformations of 2-(3-oxoindolin-2-yl)acetonitriles were investigated. Unexpectedly, attempted reactions of substrates possessing nonprotected nitrogen atoms were accompanied by unusual extrusions of 2-arylacetonitriles, followed by a 1,2-aryl shift to afford 3-hydroxyindolin-2-ones. On the other hand, the reactions for N-alkyl derivatives of oxoindolines took the expected route by only providing 1,2,3,3a,4,8b-hexahydropyrrolo[3,2-b]indoles.

Direct Conversion of 3-(2-Nitroethyl)-1H-Indoles into 2-(1H-Indol-2-yl)Acetonitriles.

The recently discovered [4+1]-spirocyclization of nitroalkenes to indoles provided a convenient new approach to 2-(1H-indol-2-yl)acetonitriles. However, this reaction was complicated by the formation of inert 3-(2-nitroethyl)-1H-indole byproducts. Herein, we offer a workaround this problem that allows for effective transformation of the unwanted byproducts into acetonitrile target molecules.

Electrophilically Activated Nitroalkanes in Double Annulation of [1,2,4]Triazolo[4,3-a]quinolines and 1,3,4-Oxadiazole Rings.

Nitroalkanes activated with polyphosphoric acid could serve as efficient electrophiles in reactions with amines and hydrazines, enabling various cascade transformations toward heterocyclic systems. This strategy was developed for an innovative synthetic protocol employing simultaneous or sequential annulation of two different heterocyclic cores, affording [1,2,4]triazolo[4,3-a]quinolines with 1,3,4-oxadiazole substituents.

[3 + 2]-Annulation of pyridinium ylides with 1-chloro-2-nitrostyrenes unveils a tubulin polymerization inhibitor.

Indolizines and pyrazolo[1,5-a]pyridines were prepared via [3 + 2]-cycloaddition of pyridinium ylides to 1-chloro-2-nitrostyrenes. The synthesized molecules were evaluated for antiproliferative activities against a BE(2)-C neuroblastoma cell line with several compounds decreasing the viability of cancer cells. Indolizine 9db showed higher potency than that of all-trans-retinoic acid, an approved cancer drug. Mechanistically, it was found to inhibit tubulin polymerization and it is thus proposed that the discovered chemistry can be exploited for the development of novel microtubule-targeting anticancer agents.

Electrophilically Activated Nitroalkanes in Synthesis of 3,4-Dihydroquinozalines.

Nitroalkanes activated with polyphosphoric acid serve as efficient electrophiles in reactions with various nucleophilic amines. Strategically placed second functionality allows for the design of annulation reactions enabling preparation of various heterocycles. This strategy was employed to develop an innovative synthetic approach towards 3,4-dihydroquinazolines from readily available 2-(aminomethyl)anilines.

Does electrophilic activation of nitroalkanes in polyphosphoric acid involve formation of nitrile oxides?

The mechanistic rationale involving activation of nitroalkanes towards interaction with nucleophilic reagents in the presence of polyphosphoric acid (PPA) was re-evaluated. Could nitrile oxide moieties be formed during this process? This experiment demonstrates that at least in some cases this could happen, as generated nitrile oxides were successfully intercepted as adducts of [3 + 2] cycloadditions.