Indole Subunits Research Articles

Tosylazide as N1-Synthon: Iron-Catalyzed Nitrogenative Dimerization of Indoles to p-Bisindolopyrazine Derivatives.

We present a straightforward one-step process to access a range of novel p-diindolepyrazines via an unprecedented [n-Bu4N][Fe(CO)3(NO)] (TBA[Fe])-catalyzed intermolecular nitrogenative dimerization of various indole derivatives. Remarkably, tosylazide functions as a N1-synthon forming the central pyrazine unit that joins the two indole subunits. The catalytic transformation shows a good substrate scope, and the obtained products show interesting electronic properties.

Total Synthesis of (+)-Alstonlarsine A: Old Reactions in Modern Alkaloids Synthesis

Abstract(+)-Alstonlarsine A is a recently isolated monoterpenoid indole alkaloid, possessing a novel pentacyclic skeleton and interesting biological activity, making it an attractive target for synthetic chemists. In this article we focus on its total synthesis, grounded on enamine formation/Diels–Alder reaction domino sequence, as well as a novel methodology for indole C2 functionalization via carbenoid insertion, which could also allow for the synthesis of other indole alkaloids possessing cycloalka[b]indole subunits.1 Introduction2 Diels–Alder Reaction3 Methodology Studies4 Total Synthesis of (+)-Alstonlarsine A by Bihelovic and Ferjancic5 Total Synthesis of (+)-Alstonlarsine A by Zhai6 Summary

Bisindole [3]arenes—Indolyl Macrocyclic Arenes Having Significant Iodine Capture Capacity

Bisindole [3]arenes—Indolyl Macrocyclic Arenes Having Significant Iodine Capture Capacity

Synthesis of new tricyclic thiolactams as potent antitumor agent for pancreatic cancer

We synthesized the novel tricyclic thiolactams 2a–d, 3d–k, having a benzyl or substituted benzyl substituent on the nitrogen of indole subunit, and their preferential cytotoxicity under both nutrient-deprived medium (NDM) and Dulbecco’s modified Eagle’s medium (DMEM) was evaluated against a human pancreatic cancer cell line PANC-1. Among the tested compounds, the 4′-hydroxy derivative 3d showed the most potent cytotoxicity in NDM (PC50 1.68μM) although the moderate preferential cytotoxicity (PC50 1.68μM in NDM vs PC50 20μM in DMEM). The 3′-hydroxy derivative 3e exhibited the most preferential cytotoxicity (PC50 1.96μM in NDM vs less than 50% inhibition at 30μM in DMEM). The benzyl 2a and halogenated benzyl derivatives 2b,c showed no cytotoxicity in NDM. In addition, the indole (10, PC50 173.7μM), lactone (11, PC50 131.7μM), and lactam (12, PC50 44.8μM) derivatives showed week or moderate cytotoxicity in NDM. These results indicated that the hydroxy group on the benzyl substituent and tricyclic thiolactam ring were essential for the cytotoxicity in NDM against PANC-1 cell line. Moreover, 3′-hydroxy derivative 3e compound exhibited antitumor activity against the pancreatic ductal adenocarcinoma (PDAC) xenograft model in vivo.

Formal synthesis of (±)-cladoniamide G

The formal synthesis of (±)-cladoniamide G, a natural product that exhibits cytotoxicity against human breast cancer MCF-7 cells, is presented. Our strategy employed a Suzuki–Miyaura coupling to join the two indole subunits of this natural product.

Porphyrin Analogues That Consist of Indole, Benzofuran, and Benzothiophene Subunits

Switching to analogue: We have designed and synthesized porphyrin analogues that consist of benzofuran, benzothiophene, and indole subunits. These cyclic benzoheterole tetramers were more stable in air and have more planar structures than the corresponding cyclic tetraindole. Photophysical and theoretical investigations revealed effective π-conjugation over the macrocyclic systems. We have designed and synthesized porphyrin analogues that consist of benzofuran, benzothiophene, and indole subunits through iridium-catalyzed CH borylation of bisbenzoheterole precursors and subsequent palladium-catalyzed cross-couplings. In the case of the benzofuran derivatives, a cyclic hexamer was also obtained. The cyclic benzoheterole tetramers were more stable in air than the corresponding cyclic tetraindole. X-ray crystallography revealed that the benzoheterole tetramers have more planar conformations than the cyclic tetraindole. Compared with the cyclic tetraindole, the lowest energy bands in the absorption spectra of the cyclic benzoheteroles are red-shifted, which shows the effective expansion of π-conjugation. 1 As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Indole substituted zinc phthalocyanine: Improved photosensitizing ability and modified photooxidation mechanism

The photophysical and photochemical processes within a novel photosensitizer (PS), zinc phthalocyanine (ZnPc) modified by indole units, were explored. The properties related to photodynamic therapy of tumor (PDT) were studied by time-resolved transient UV–vis absorption spectra, steady state and time-resolved fluorescence spectra, and chemical trapping of singlet oxygen by diphenylisobenzofuran (DPBF). Intra-molecular photoinduced electron transfer (PET) within the conjugate from the indole subunits (donor A), to S 1 (excited singlet state) of ZnPc moiety (acceptor D), is featured by the significant decrease of fluorescence quantum yield and lifetime of ZnPc moiety, and the occurrence of transient absorption bands of ZnPc − at 570 and 630 nm. The triplet state, on the other hand, was not quenched by indole units. The kinetics and thermodynamics of PET were analyzed quantitatively, and the quantum efficiency of PET is computed to be 38%, almost double of the emission efficiency (20%). The quantum efficiency of triplet (T 1) formation is 0.50 and the quantum yield of DPBF photooxidation is 0.72. Both are larger than the expected value of 0.32. The evolution of transient absorption spectra showed that the charge separation state (ZnPc −–indole +) recombined to triplet state ZnPc(T 1)–indole, which is responsible for the high yield of T 1 formation. In the presence of oxygen, both T 1 and ZnPc − were quenched efficiently, which forms singlet oxygen and superoxide anion, respectively. DPBF is therefore photo-oxidized by both singlet oxygen (Type II reaction, 46%) and superoxide anion radical (Type I reaction, 54%), which led to the high yield of photooxidation. This is in contrast to free ZnPc PS, in which only singlet oxygen is responsible for the photooxidation. The result suggests that the reaction mechanism is changed upon conjugation so that the importance of Type I reaction is greatly enhanced, and the indole-conjugated ZnPc is an even better PS than the free ZnPc.

Azomethine ylide annulations: facile access to polycyclic ring systems

New annulation reactions of azomethine ylides are reported. Amino acids react with aldehydes that are linked to a pronucleophile (e.g. an indole subunit) to provide rapid access to polycyclic ring systems. Simple amines can also be used in place of amino acids.

Infrared Spectra of Protonated Neurotransmitters: Serotonin

The gas-phase IR spectrum of the protonated neurotransmitter serotonin (5-hydroxytryptamine) was measured in the fingerprint range by means of IR multiple photon dissociation (IRMPD) spectroscopy. The IRMPD spectrum was recorded in a Fourier transform ion cyclotron resonance mass spectrometer coupled to an electrospray ionization source and an IR free electron laser. Quantum chemical calculations at the B3LYP and MP2 levels of theory using the cc-pVDZ basis set yield six low-energy isomers in the energy range up to 40 kJ/mol, all of which are protonated at the amino group. Protonation at the indole N atom or the hydroxyl group is substantially less favorable. The IRMPD spectrum is rich in structure and exhibits 22 distinguishable features in the spectral range investigated (530-1885 cm(-1)). The best agreement between the measured IRMPD spectrum and the calculated linear IR absorption spectra is observed for the conformer lowest in energy at both levels of theory, denoted g-1. In this structure, one of the three protons of the ammonium group points toward the indole subunit, thereby maximizing the intramolecular NH(+)-π interaction between the positive charge of the ammonium ion and the aromatic indole ring. This mainly electrostatic cation-π interaction is further stabilized by significant dispersion forces, as suggested by the substantial differences between the DFT and MP2 energies. The IRMPD bands are assigned to individual normal modes of the g-1 conformer, with frequency deviations of less than 29 cm(-1) (average <13 cm(-1)). The effects of protonation on the geometric and electronic structure are revealed by comparison with the corresponding structural, energetic, electronic, and spectroscopic properties of neutral serotonin.

Synthesis-driven mapping of the dictyodendrin alkaloids

The dictyodendrin alkaloids have been described as the first telomerase inhibitors of marine origin. As such they represent interesting lead compounds in the quest for small molecule inhibitors of this tumor-marker enzyme. Described herein is the preparation of a collection of dictyodendrin-like compounds that hinges on the formation of their indole subunit by reductive cyclization of appropriate keto-amide precursors mediated by low valent titanium. It is shown that the underlying concept can be extended from the synthesis of heterocycles to the preparation of phenol and aniline derivatives using oxo-acid, oxo-nitrile or oxo-lactam derivatives as the substrates; such arene formations can even be carried out in cascade. Exploratory studies into the closure of the B-ring of the dictyodendrins with the aid of electrophilic reagents such as Ph 3PAuCl/AgSbF 6 or I + revealed the bias of these polycyclic heteroarenes to undergo unusual skeletal rearrangements. It is demonstrated that the individual dictyodendrins and analogues are capable of cleaving double stranded DNA under oxidative conditions, provided that they exhibit at least one unprotected phenol group in their periphery.

Enantioselective Synthesis of (−)‐(19R)‐Ibogamin‐19‐ol

AbstractThe first total synthesis of the natural product (−)‐(19R)‐ibogamin‐19‐ol ((−)‐1) is reported (biogenetic atom numbering). Starting with L‐glutamic acid from the chiral pool and (2S)‐but‐3‐en‐2‐ol, the crucial aliphatic isoquinuclidine (= 2‐azabicyclo[2.2.2]octane) core containing the entire configurational information of the final target was prepared in 15 steps (overall yield: 15%). The two key steps involved a highly effective, self‐immolating chirality transfer in an Ireland–Claisen rearrangement and an intramolecular nitrone‐olefin 1,3‐dipolar cycloaddition reaction (Scheme 3). Onto this aliphatic core was grafted the aromatic moiety in the form of N(1)‐protected 1H‐indole‐3‐acetic acid by application of the dicyclohexylcarbodiimide (DCC) method (Scheme 4). Four additional steps were required to adjust the substitution pattern at C(16) and to deprotect the indole subunit for the closure of the crucial 7‐membered ring present in the targeted alkaloid family (Schemes 4 and 5). The spectral and chiroptical properties of the final product (−)‐1 matched the ones reported for the naturally occurring alkaloid, which had been isolated from Tabernaemonatana quadrangularis in 1980. The overall yield of the entire synthesis involving a linear string of 20 steps amounted to 1.9% (average yield per step: 82%).

Short, Enantioselective Total Synthesis of Okaramine N.

The first enantioselective total synthesis of a member of the okaramine family of bis-indole alkaloids, okaramine N (1), has been accomplished via intermediates 2-7, as outlined. The N-prenylated derivative of (S)-tryptophan methyl ester (2) was coupled with Fmoc-protected N-tert-prenylated tryptophan (3) to form the amide 4 in 70% yield. Pd(II)-mediated cyclization/rearrangement, a key step in the synthesis, transformed 4 into the indoloazacine 5 (44%), which was deprotected and cyclized in a single step to give the hexacyclic diketopiperazine 6 (95%). In the following novel and key sequence, 6 was transformed into 1: (1) selective ene reaction with N-methyltriazolinedione, (2) photooxidation of the remaining tert-prenylated indole subunit to provide 7, and (3) thermal retroene reaction of 7 to afford okaramine N (70% from 6).

Short, enantioselective total synthesis of okaramine N.

The first enantioselective total synthesis of a member of the okaramine family of bis-indole alkaloids, okaramine N (1), has been accomplished via intermediates 2-7, as outlined. The N-prenylated derivative of (S)-tryptophan methyl ester (2) was coupled with Fmoc-protected N-tert-prenylated tryptophan (3) to form the amide 4 in 70% yield. Pd(II)-mediated cyclization/rearrangement, a key step in the synthesis, transformed 4 into the indoloazacine 5 (44%), which was deprotected and cyclized in a single step to give the hexacyclic diketopiperazine 6 (95%). In the following novel and key sequence, 6 was transformed into 1: (1) selective ene reaction with N-methyltriazolinedione, (2) photooxidation of the remaining tert-prenylated indole subunit to provide 7, and (3) thermal retroene reaction of 7 to afford okaramine N (70% from 6).

Binding-Induced Activation of DNA Alkylation by Duocarmycin SA: Insights from the Structure of an Indole Derivative−DNA Adduct

The mechanism for catalysis of DNA alkylation by the potent antitumor antibiotic duocarmycin SA (DSA) has been probed by determining the structure of a DNA adduct of the indole analogue (DSA-indole, DSI) lacking three methoxy functional groups. The three-dimensional structure of DSI covalently bound to A19 in d-(G1ACTAATTGAC11)·d-(G12TCAATTAGTC22) was determined by 1H NMR spectroscopy using a total of 935 experimental distance and dihedral angle constraints. The representative ensemble of 20 conformers has no distance restraint violations greater than 0.03 A, no torsional restraint violations greater than 0.7°, and a pairwise rmsd over all atoms in the binding site of 0.48 A. Comparison of the structures of the DSA and DSI adducts reveals a structural basis for the critical role of one of the trimethoxy-indole functional groups in alkylation reactivity. A deeper penetration into the DNA minor groove in the vicinty of the indole subunit is observed for the DSI versus the DSA adduct, along with some variati...

Synthesis of 2-hetaryl substituted indoles via palladium-catalysed reductive N-heterocyclisation

An improved synthesis of a family of polidendate ligands embodying indole subunit(s) was performed, via a nitrene insertion as a key step, starting from easily accessible o-nitrostyryl precursors. This transformation was efficiently achieved through the agency of CO in the presence of Pd(2,4,6-trimethylbenzoate) 2 as catalyst and 3,4,7,8-tetramethyl-1,10-phenanthroline as co-ligand.

Design of receptors for urea derivatives based on the pyrido[3,2-g]indole subunit

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTDesign of receptors for urea derivatives based on the pyrido[3,2-g]indole subunitVidyadhar Hegde, Chi Ying Hung, Puttannachetty Madhukar, Raymond Cunningham, Thomas Hopfner, and Randolph P. ThummelCite this: J. Am. Chem. Soc. 1993, 115, 3, 872–878Publication Date (Print):February 1, 1993Publication History Published online1 May 2002Published inissue 1 February 1993https://doi.org/10.1021/ja00056a008RIGHTS & PERMISSIONSArticle Views743Altmetric-Citations70LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (944 KB) Get e-AlertsSupporting Info (3)»Supporting Information Supporting Information Get e-Alerts

Molecular basis for sequence-specific DNA alkylation by CC-1065.

CC-1065 is a potent antitumor antibiotic that binds covalently to N3 of adenine in the minor groove of DNA. The CC-1065 molecule is made up of three repeating pyrroloindole subunits, one of which (the left-hand one or A subunit) contains a reactive cyclopropyl function. The drug reacts with adenines in DNA in a highly sequence-specific manner, overlapping four base pairs to the 5'-side of the covalently modified base. Concomitant with CC-1065 covalent binding to DNA is an asymmetric effect on local DNA structure which extends more than one helix turn to the 5'-side of the covalent binding site. The DNA alkylation, sequence specificity, and biological potency of CC-1065 and a select group of trimeric synthetic analogues were evaluated. The results suggest that (a) noncovalent interactions between this series of compounds and DNA do not lead to the formation of complexes stable enough to be detected by footprinting methods, (b) sequence specificity and alkylation intensity can be modulated by the substituents on the nonreactive middle and right-hand segments, and (c) biological potency correlates well with ability to alkylate DNA. In addition, the extent and the sequence specificity of covalent adduct formation between linear DNA fragments and three analogues comprised of the CC-1065 alkylating subunit linked to zero (analogue A), one (analogue AB), or two (analogue ABC) nonreactive indole subunits were compared.(ABSTRACT TRUNCATED AT 250 WORDS)

Eine neue synthese von vinblastin-derivaten II : Synthesekonzept und modelluntersuchungen

Starting from vindoline ( 2 ) and 7-methoxycarbonylazoninoindole derivatives 7 , a new concept for the synthesis of vinblastine 1a type alkaloids with natural C(16') stereochemistry is described. Using lactam 8 and chloroindolenine 9 as key intermediatea a stereocontrolled coupling between the dihydroindole and indole subunits under formation of 10 should be achieved. Methanolysis of 10 and intramolecular No-alkylation of the resulting 12a should lead to 20 - ́ deethyl-20'-deoxyvinblastine 13a . Model investigations for the synthesis of lactam 8 are described. A new method for the introduction of the nitrile group into the α-position of 2-alkylindoles using α-hydroxyalkyl substituted derivatives as starting materials is presented.

The synthesis of indole subunits for CC-1065

A four-step preparation of the benzodipyrroles (5) and (7) from the quinone di-imine (2) is described.