Regioselective Intramolecular Reactions of 2-Indolylacyl Radicals with Pyridines:  A Direct Synthetic Entry to Ellipticine Quinones

Bennasar, M.‐Lluïsa; Roca, Tomas; Ferrando, Francesc

doi:10.1021/jo0514974

Cited by 51 publications

(26 citation statements)

References 31 publications

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“…Refluxing this intermediate in o -xylene provided the core thienopyrroles in good yields 25. Several techniques proved capable of installing the needed aldehyde functionality, but ultimately we relied upon a Vilsmeier-Haack reaction to form the substituted ethyl 6-formyl-4H-thieno[3,2-b]pyrrole-5-carboxylates 26. There was no indication of alternate regiochemical formyl installation.…”

mentioning

confidence: 99%

Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase

Jiang

Boxer

Heiden

et al. 2010

Bioorganic & Medicinal Chemistry Letters

116

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Cancer cells have distinct metabolic needs that are different from normal cells and can be exploited for development of anti-cancer therapeutics. Activation of the tumor specific M2 form of pyruvate kinase (PKM2) is a potential strategy for returning cancer cells to a metabolic state characteristic of normal cells. Here, we describe activators of PKM2 based upon a substituted thieno[3,2-b]pyrrole[3,2-d]pyridazinone scaffold. The synthesis of these agents, structure activity relationships, analysis of activity at related targets (PKM1, PKR and PKL) and examination of aqueous solubility are investigated. These agents represent the second reported chemotype for activation of PKM2.

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mentioning

confidence: 99%

Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase

Jiang

Boxer

Heiden

et al. 2010

Bioorganic & Medicinal Chemistry Letters

116

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“…The precipitate was collected by filtration, washed with cooled water and dried in vacuo . Compounds 7a , 7 b , 7d and 7e are known (see references 29 , 32 , 33 ).…”

Section: Methodsmentioning

confidence: 99%

“…The crude residue was suspended in petroleum ether, the mixture stirred for 15 min and then filtered to afford the corresponding N -methyl, N -ethyl or N -benzyl 2-alkoxycabonyl-3-formyl indole derivatives 8a–d , 8e–h and 8i–l , respectively, which was used for the next reaction without further purification. Compounds 8a , 8 b and 8i are known (see references 32 , 34 , 35 ).…”

Section: Methodsmentioning

confidence: 99%

Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach

Preti

Romagnoli

Rondanin

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3′,4′,5′-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC50 values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3′,4′,5′-trimethoxyphenyl)-2-propen-1-one framework. The structure–activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC50 values of 0.37, 0.16 and 0.17 μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC50: 18 μM). This derivative also displayed cytotoxic properties (IC50 values ∼1 μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G2-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3′,4′,5′-trimethoxyphenyl scaffold.

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“…It was gratifying that the compound 11 gave indole 12 quantitatively simply by heating at reflux in toluene. The Vilsmeier formylation [10] was performed and aldehyde 13 was obtained in 56% yield (with 40% recovery of 12) Condensation of aldehyde 13 with nitromethane was carried out according to the procedure of Young [11a] and Rodríguez [11b] and the subsequent olefin reduction was feasible by using NaBH 4 [11b,11c,11d] to give nitro compound 14 with an intact nitro group in 76% overall yield [12]. Reduction of the nitro group of 14 was carried out by hydrogenation with Pd/C and the resulting tryptamine was immediately protected by a benzoyl group in order to avoid the problematic lactam formation, affording the desired benzamide 15 in 77% yield.…”

Section: Synthesis Of 67-dimethoxy-5-methoxymethoxy-1h-indole (1)mentioning

confidence: 99%

Synthesis of the indole core structures of conophylline

Ando

Okamoto

Otsuka

et al. 2008

Journal of Heterocyclic Chem

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Regioselective Intramolecular Reactions of 2-Indolylacyl Radicals with Pyridines: A Direct Synthetic Entry to Ellipticine Quinones

Cited by 51 publications

References 31 publications

Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase

Evaluation of thieno[3,2-b]pyrrole[3,2-d]pyridazinones as activators of the tumor cell specific M2 isoform of pyruvate kinase

Design, synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach

Synthesis of the indole core structures of conophylline

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