Tetracyclic Indole Research Articles

NAD+‐dependent DNA ligase (Rv3014c) from Mycobacterium tuberculosis: Novel structure‐function relationship and identification of a specific inhibitor

Mycobacterium tuberculosis codes for an essential NAD+-dependent DNA ligase (MtuLigA) which is a novel, validated, and attractive drug target. We created mutants of the enzyme by systematically deleting domains from the C-terminal end of the enzyme to probe for their functional roles in the DNA nick joining reaction. Deletion of just the BRCT domain from MtuLigA resulted in total loss of activity in in vitro assays. However, the mutant could form an AMP-ligase intermediate that suggests that the defects caused by deletion of the BRCT domain occur primarily at steps after enzyme adenylation. Furthermore, genetic complementation experiments using a LigA deficient E. coli strain demonstrates that the BRCT domain of MtuLigA is necessary for bacterial survival in contrast to E. coli and T. filiformis LigA, respectively. We also report the identification, through virtual screening, of a novel N-substituted tetracyclic indole that competes with NAD+ and inhibits the enzyme with IC50 in the low muM range. It exhibits approximately 15-fold better affinity for MtuLigA compared to human DNA ligase I. In vivo assays using LigA deficient S. typhimurium and E. coli strains suggest that the observed antibacterial activity of the inhibitor arises from specific inhibition of LigA over ATP ligases in the bacteria. In silico ligand-docking studies suggest that the exquisite specificity of the inhibitor arises on account of its mimicking the interactions of NAD+ with MtuLigA. An analysis of conserved water in the binding site of the enzyme suggests strategies for synthesis of improved inhibitors with better specificity and potency.

Arboricine (I) and Arboricinine (II), Unusual Tetracyclic Indole Regioisomers from Kopsia.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Arboricine and arboricinine, unusual tetracyclic indole regioisomers from Kopsia

A pair of unusual regioisomeric tetracyclic indoles of the corynantheine-type, arboricine and arboricinine were obtained from the Malayan Kopsia arborea. The structures were established by spectroscopic analysis and a possible biogenetic link between the alkaloids is presented.

Modular Synthesis of Fused Indole Derivatives

Complementary routes to strained doubly cycloalkyl-fused indole derivatives using modern cross-coupling methodology are reported. Stille coupling of 7-stannylated indoline with 2-iodo cyclic enones leads to the key intermediate A which, by reduction and LiHMDS-mediated triflation using Comins’ excellent reagent, gives isomeric triflates. The latter compounds are deprotected and transformed to the tetracyclic indole derivative B by the Buchwald-Hartwig C-N coupling tactic or, directly, by acid-catalyzed cyclization. The overall yields are reasonable but the scope in terms of benzene-moiety substitution and variable cycloalkyl ring size remains to be explored.

Synthesis and Cytotoxicity Studies of Cyclohepta[b]indoles, Benzo[6,7]Cyclohepta[1,2-b]Indoles, Indeno[1,2-b]Indoles, and Benzo[a]Carbazoles

Synthesis and biological evaluation of various tricyclic and tetracyclic indoles are described. A number of these compounds possess in vitro activity against human nasopharyngeal carcinoma (HONE-1) and gastric adenocarcinoma (NUGC-3) cell lines.

Discovery of indole-containing tetracycles as a new scaffold for androgen receptor ligands

A novel series of tetracyclic indoles have been designed, synthesized and evaluated as androgen receptor (AR) ligands. Studies of structure–activity relationships (SARs) were investigated, which led to some compounds in this series as strong binders to androgen receptors.

Determining the scope of the lanthanide mediated, sequential hydroamination/C–C cyclization reaction: formation of tricyclic and tetracyclic aromatic nitrogen heterocycles

The scope of the lanthanide mediated, sequential hydroamination/C–C cyclization reaction was determined for the formation of tricyclic and tetracyclic aromatic nitrogen heterocycles. An array of ring sizes was explored to determine the diastereoselectivity. The electronic characteristics of the aromatic ring was also varied to determine how it affected the cascade reaction. It was found that the benzo[a]quinolizine and the pyrido[2,1,a]isoindolizine ring systems formed with the highest diastereoselectivity (>20:1), regardless of the electronic characteristics of the aromatic ring. Additionally, a tetracyclic indole nitrogen heterocycle was formed with a 2.3:1 diastereomeric ratio. A novel procedure for substrate preparation is also presented.

Asymmetric synthesis of (-)-eburnamonine and (+)-epi-eburnamonine from (4S)-4-ethyl-4-[2-(hydroxycarbonyl)ethyl]-2-butyrolactone.

The key chiral nonracemic 4,4-disubstituted 2-butyrolactone carboxylic acid, (S)-4, is readily accessible via an efficient and stereospecific dirhodium(II) tetraacetate catalyzed tertiary C-H insertion reaction of the diazomalonate (S)-5. The coupling of the acid (S)-4 with tryptamine produces the amide (S)-3, which is then transformed into the aldehyde 23 and hydroxy-lactam 24. Acid-mediated Pictet-Spengler cyclization of 23 and 24 produces the tetracyclic indole lactams (1S,12bS)-25a and (1S,12bR)-25b. Compounds 25a and 25b are converted, via the lactam alcohols 30a and 30b, to (-)-eburnamonine (1a) and (+)-epi-eburnamonine (1b).

ChemInform Abstract: Hydrogen Bonding in Two Tetracyclic Indole Alkaloids.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Hydrogen bonding in two tetracyclic indole alkaloids.

3-Acetyl-1,6,7,12b-tetrahydroindolo[2,3-a]quinolizin-2(12H)-one, C17H16N2O2, consists of two symmetry-independent molecules and each forms a layered structure stabilized by N-H...O and C-H...O hydrogen bonds. In 3-acetyl-6,7-dihydroindolo[2,3-a]quinolizin-4(12H)-one monohydrate, C17H14)N2O2.H2O, the structure is stabilized by O-H...O, N-H...O and C-H...O hydrogen bonds, with the ordered water molecule playing a crucial role in the self-assembly. Contribution from the weak interactions to the strong hydrogen-bonded network is a common feature in both structures.

ChemInform Abstract: Pictet-Spengler Reaction: Is Carbonyl the Best Choice? A Highly Diastereoselective Alternative Approach to trans-1,3-Disubstituted Tetrahydro-β-carbolines.

Abstract Unprecedented 1,2,3-trisubstituted tetrahydro-β-carbolines (THBCs) have been synthesized via a short and highly diastereoselective synthetic route. The key step of the sequence is a flexible variant of the Pictet–Spengler reaction employing synthetic equivalents of several non-available carbonyl compounds. Using one such synthon, the resultant THBC could be further ring-closed to a tetracyclic indole alkaloidal skeleton.

Pictet–Spengler reaction: is carbonyl the best choice? A highly diastereoselective alternative approach to trans-1,3-disubstituted tetrahydro-β-carbolines

Unprecedented 1,2,3-trisubstituted tetrahydro-β-carbolines (THBCs) have been synthesized via a short and highly diastereoselective synthetic route. The key step of the sequence is a flexible variant of the Pictet–Spengler reaction employing synthetic equivalents of several non-available carbonyl compounds. Using one such synthon, the resultant THBC could be further ring-closed to a tetracyclic indole alkaloidal skeleton.

Studies towards understanding the mechanism of the unusual rearrangement of certain 5-propargyloxyindoles

A mechanism of the rearrangement of 5-propargyloxyindoles is proposed and supported by the formation of a novel tetracyclic indole derivative 12 as the major product in the cyclization of 5-propargyloxytryptophol 10.

Intermediates for the synthesis of indole alkaloids. Synthesis of tetrahydrocarbazole derivatives

AbstractThe synthesis of new precursors 8 and 15 for the synthesis of tetracyclic indole alkaloids were described. Many new intermediates 4‐7 and 9‐14 have also been synthesized.

ChemInform Abstract: Intermediates for the Synthesis of Tetracyclic Indole Alkaloids. Synthesis of 4‐Aminotetrahydrocarbazole Derivatives.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Photochemistry of the Nitrogen-Thiocarbonyl Systems, Part 31. Photoreaction of Arenecarbothioamides with 2-Vinylfuran Analogues. The Formation of Tetracyclic Indoles and 2,3-Diaryl-2-pyrrolin-5-ones.

Photoreaction of arenecarbothioamides (1) with 2-vinylfuran analogues (2, 6) in benzene aolution gave tetracyclic indole systems (3, 8) via photogenerated diarylethylene intermediates. In the case of reaction of furan- or thiophenecarbothioamide (1c, 1d) with 2-furanacrylic acid (2-i), 2, 3-diaryl-2-pyrrolin-5-ones (5c-i, 5d-i) were obtained.

Intermediates for the synthesis of tetracyclic indole alkaloids. Synthesis of 4‐aminotetrahydrocarbazole derivatives

AbstractAn efficient method for the synthesis of 4‐aminotetrahydrocarbazole derivatives from 2,3‐dihydrospiro‐[1H‐carbazole‐1,2′‐(1,3)‐dithiolan]‐4‐(9H)‐one 1 is described. The structure of compound 6 has been confirmed by X‐ray structure analysis.

ChemInform Abstract: Asymmetric Synthesis of Highly Functionalized Tetracyclic Indole Bases Embodying the Basic Skeleton of Yohimbine‐ and Reserpine Type Alkaloids.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Asymmetric synthesis of highly functionalized tetracyclic indole bases embodying the basic skeleton of yohimbine- and reserpine type alkaloids

Schiff bases derived from tryptophan methyl ester react with differently substituted electron-rich siloxy dienes in the presence of achiral or chiral boric acid esters to give enaminones 5 and 6 with high diastereomer ratios (up to >98:2). These intermediates are converted into highly functionalized indoloquinolizines 14 and 15 by means of a new method which employs the transformation of vinylogous amides to vinylogous chloromethyl amines and their subsequent conversion to vinylogous imidoyl chlorides as the key step.

Construction of tetracyclic indole bases via Aza Diels‐Alder reaction of indolylethylimines with Brassard's diene

AbstractSchiff's bases 3 derived from tryptamine react with Brassard's diene 4 in the presence of EtAlCl2 to give functionalized 1,2,5,6‐tetrahydropyridines which are subsequently transformed to indolo[2,3‐a]quinolizines 8–10 by the Bischler‐Napieralski reaction and reduction of the intermediate iminium salts with NaBH4. magnified image