Synthesis of 6<i>H</i>-Indolo[2,3-<i>b</i>][1,6]naphthyridines and Related Compounds as the 5-Aza Analogues of Ellipticine Alkaloids

Zhang, Quan; Shi, Chongsheng; Zhang, Hai‐Ren; Wang, Kung K.

doi:10.1021/jo000978e

Cited by 87 publications

(51 citation statements)

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“…In the calculation of the structure of 12B, the bond distance between O and P was 2.943 Å, and this lies midway between O-P covalent bond (1.79 Å) and van der Waals radius of O and P (3.30 Å). It is reported that phospa-oxa-azulene (14) showed the bond lengths 2.00-2.36 Å. [22][23][24] Although the bond distance of 12B is longer than those of 14, above results suggest that 12 exists as resonance hybrid of 12B.…”

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confidence: 73%

“…We previously reported that reaction of 2-(triphenylphosphoimino)-1-azaazulene with aryl isocyanate proceeded via 2-aryl 1-azaazulen-2-yl carbodiimide intermediate. It is known that enyne-carbodiimides proceeded cyclization to give heteroaromatics such as carbolines and ellipticine analogues, [11][12][13][14][15][16][17] and underwent Pouson-Khand type reaction in the presence of Mo(CO) 6 . 26 Therefore, we next examined the reaction of 8 with aryl isocyanate.…”

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confidence: 99%

“…10 In the recent studies about heteroaromatics such as carbolines and ellipticine analogues, benzannulated enyne-carbodiimides and o-ethynylaryliminophosphoranes were used as key intermediates. [11][12][13][14][15][16][17] In the line of our studies about 1-azaazulenes, [18][19][20] we investigated the synthesis and reaction of 3-ethynyl-2-(triphenylphosphoimino)-1-azaazulenes.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Reactions of 3-Ethynyl-2-(triphenylphosphoimino)-1-azaazulenes

Abe¹,

Nagamatsu²,

Ariyoshi³

et al. 2007

HETEROCYCLES

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-3-(Trimethylsilylethynyl)-and 3-(phenylethynyl)-2-(triphenylphosphoimino)-1-azaazulenes were synthesized by the Appel reaction of the corresponding 2-amino-3-ethynyl-1-azaazulenes. Reaction of 3-(phenylethynyl)-2-(triphenylphosphoimino)-1-azaazulene (8b) with Cu(OTf) 2 gave 3-(2-oxophenethyl)-2-(triphenylphosphoimino)-1-azaazulene (11), 3-(1,2-dioxophenethyl)-2-(triphenylphosphoimino)-1-azaazulene (12), and 2-amino-3-(1,2-dioxophenethyl)-1-azaazulene (13). The structure of 13 was decided by X-ray structure analysis, and the structure of 12 was discussed by molecular orbital calculation. Reaction of 8b with aryl isocyanate in the presence of benzoyl peroxide gave 1,10-diazabenz[a]azulene derivative. INTRODUCTIONIt is known that the iminophosphoranes, chemical species having the nitrogen-phosphorus double bond, reveal synthetic versatility for the construction of fused heterocycles.

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confidence: 73%

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confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis and Reactions of 3-Ethynyl-2-(triphenylphosphoimino)-1-azaazulenes

Abe¹,

Nagamatsu²,

Ariyoshi³

et al. 2007

HETEROCYCLES

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“…Carbodiimide is considered to be an aza-equivalent of allene, and more importantly, canceled dipole moments of C-N bonds are expected to facilitate the homolytic cleavage of the C-N bond to form radical species. The Wang [24][25][26][27][28] and the Schmittel 29-31) groups have recently reported the thermal CA of AYCs, but their scopes are limited to conjugated systems, whose electronic and steric environments are far different from nonconjugated ones, and which would be unable to provide dibenzonaphthyridine derivatives. Herein, we report the synthesis and the CA reactions of AYCs 1 and 2.…”

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confidence: 99%

Thermal Cyclization of Nonconjugated Aryl-Yne-Carbodiimide Furnishing a Dibenzonaphthyridine Derivative

Kimura

Torikai

Ueda

2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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NotesConjugated enyne compounds have received considerable attention in the broad field of chemistry, because of their unique cyclization reactions affording aromatized products by way of radical intermediates capable of DNA cleavage. [2][3][4][5][6][7][8] To date, a number of polyenyne compounds, including both natural 2,4,7) and artificial products, 3,7,8) have been synthesized to evaluate their reactivity and to develop more potent and selective antitumor agents, however, modification of the conjugated enyne core structures has not been well investigated. We focused on nonconjugated polyenyne systems and found that nonconjugated aryl-ynes and aryl-yne-allenes undergo thermal cycloaromatization (CA) reactions [9][10][11][12][13][14] while cleaving DNA. [15][16][17] Thus, as a next goal, we set a reagent-free thermal isomerization of nonconjugated aryl-yne systems, which involves homolyses of carbon-nitrogen (C-N) unsaturated bonds to afford useful azaaromatic compounds via a domino radical reaction. 18)As target polycyclic aromatic compounds, we focused on dibenzonaphthyridine derivatives, which have never been synthesized via thermal isomerization of aryl-ynes, despite their fascinating and intriguing pharmacological properties. [19][20][21][22][23] In order to provide a novel synthetic methodology of dibenzonaphthyridines, we planned to examine the CA reactions of nonconjugated aryl-yne-carbodiimides (AYCs). Carbodiimide is considered to be an aza-equivalent of allene, and more importantly, canceled dipole moments of C-N bonds are expected to facilitate the homolytic cleavage of the C-N bond to form radical species. The Wang [24][25][26][27][28] and the Schmittel 29-31) groups have recently reported the thermal CA of AYCs, but their scopes are limited to conjugated systems, whose electronic and steric environments are far different from nonconjugated ones, and which would be unable to provide dibenzonaphthyridine derivatives. Herein, we report the synthesis and the CA reactions of AYCs 1 and 2.As AYC substrates, we selected two compounds (Fig. 1). One possesses a conjugated aryl-yne and a dependent carbodiimide moiety (1) and the other is equipped with a conjugated aryl-carbodiimide and a dependent alkyne moiety (2).Synthesis of AYC 1 commenced with 2-bromobenzylamine hydrochloride 3 (Chart 1). After tert-butoxycarbonyl (Boc) protection of 3 (98%), the resulting bromobenzene 4 was coupled with ethynylbenzene 5 under Sonogashira-Hagihara conditions 32,33) to give 6 in good yield (90%). 34) After removal of the Boc group with trifluoroacetic acid (TFA), amine 7 was converted to the corresponding thiourea 8 by the action of phenyl isothiocyanate in refluxing acetone (69%).35) Desulfurization of 8 by treatment with methanesulfonyl chloride (MsCl) in the presence of triethylamine and 4-dimethylaminopyridine (DMAP) 36) successfully furnished carbodiimide 1 (84%). As for AYC 2, the synthesis was initiated with 2-aminobenzylalcohol 9. Oxidation of alcohol 9 with MnO 2 into aldehyde, followed by addition of phenyleth...

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“…The synthesis of the 1-chloro-5-aza-ellipticine (7) was accomplished in six steps with a 6.7% overall yield (Scheme 1) using a modification of the procedure developed by Zhang et al 7,14,15 The precursor 4 16 was converted to the isocyanate 5 using triphosgene. 17 The radical cycloaddition of 5 with phosphorane 6 occurs at elevated temperature and is accompanied by precipitation of triphenylphosphine oxide.…”

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confidence: 99%

Synthesis and biological activity of 5-aza-ellipticine derivatives

Moody¹,

Dyba²,

Kosakowska-Cholody³

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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Novel 5-aza-ellipticine derivatives were synthesized and tested as antitumor agents. The new compounds were prepared more readily than the analogous ellipticine derivatives, which are known to be potent anti-tumor agents Although the novel 5-aza-ellipticine derivatives are not as biologically active as their corresponding ellipticine analogues, the new compounds represent a new, readily accessible class of heteroaromatic catalytic inhibitors of topoisomerase II and possible anti-tumor agents.Keywords 5-Aza-ellipticine; Anti-tumor agents; Topoisomerase II; Ellipticine Ellipticine (1) was first identified in 1959 as a compound in the leaves of an Australian evergreen, Ochrosia elliptica labil (Apocynaceae family). 1 Ellipticine is one of many carbazole alkaloids that exhibit biological, especially anti-tumor, activities. 2 Many synthetic variants of the natural product were made and tested for anti-tumor activity. The most likely target of ellipticine is topoisomerase II, whose inhibition results in the observed cytotoxicity. However, the low water solubility of ellipticine at physiological pH, as well as its systemic toxicity, prevents its use as a therapeutic agent. Several simple structural modifications to ellipticine derivatives gave compounds with increased toxicity (such as a methoxy substituent at the C9 position and a methyl substituent at the C11 position). 3,4Previously, the novel ellipticine derivative (2) was coupled to heptagastrin, which binds with high affinity to the gastrin/cholecystokinin type B receptor. 5 The hypothesis was that since CCK-B receptors are over-expressed in some gastrointestinal cancers, 6 the heptagastrin conjugate could be delivered very selectively to CCK-B positive cancer cells by receptormediated endocytosis. We demonstrated that heptagastrin conjugate was delivered to lysozomes in CCK-B receptor positive cells where it was processed to release the cytotoxic ellipticine derivative. Compound 2 is cytotoxic to tumor cells at low nanomolar concentrations but is relatively nonselective, while the heptagastrin conjugate, while slightly less toxic to sensitive cells, was completely selective to only those cells that expressed the CCK-B receptor. Compound 2 was synthesized in thirteen steps with an overall 7% yield. Recently, Zhang et al. 7 reported the synthesis of 5-aza analogues of ellipticines (3) via an interesting radical cyclization reaction. We wished to examine the anti-tumor properties of these novel compounds because their synthesis was more readily accomplished than the original ellipticines and because they offered the possibility of additional elaboration of the original structures. In this study, novel 5-aza-ellipticine derivatives were synthesized, which contain a C9 methoxy substituent and a C11 methyl substituent. Consistent with known structure-activity relationships of ellipticine, many of these novel 5-aza-ellipticine derivatives inhibited the growth of HCT116 cells, with approximately the same potency as ellipticine.The synthesis of the 1-chloro-5-aza...

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Synthesis of 6H-Indolo[2,3-b][1,6]naphthyridines and Related Compounds as the 5-Aza Analogues of Ellipticine Alkaloids

Cited by 87 publications

References 38 publications

Synthesis and Reactions of 3-Ethynyl-2-(triphenylphosphoimino)-1-azaazulenes

Synthesis and Reactions of 3-Ethynyl-2-(triphenylphosphoimino)-1-azaazulenes

Thermal Cyclization of Nonconjugated Aryl-Yne-Carbodiimide Furnishing a Dibenzonaphthyridine Derivative

Synthesis and biological activity of 5-aza-ellipticine derivatives

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