Synthesis of 6- or 4-functionalized indoles via a reductive cyclization approach and evaluation as aromatase inhibitors

Lézé, Marie-Pierre; Palusczak, Anja; Hartmann, Rolf W.; Borgne, Marc Le

doi:10.1016/j.bmcl.2008.06.094

Cited by 35 publications

(3 citation statements)

References 23 publications

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“…Comparing (−)-( S )- 8g with letrozole, the most potent non-steroidal inhibitor (IC 50 = 0.025 nM), there was no significant activity for our antifungal agent against CYP19. In the opposite way, all works undertaken around the indole and the design of non-steroidal aromatase inhibitors [ 18 , 19 , 32 , 33 , 34 , 35 , 36 ] helped us to design our first antifungal azolyl-substituted indoles [ 22 , 23 ].…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Optimization, Antifungal Activity, Selectivity, and CYP51 Binding of New 2-Aryl-3-azolyl-1-indolyl-propan-2-ols

Lebouvier

Pagniez

et al. 2020

Pharmaceuticals

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A series of 2-aryl-3-azolyl-1-indolyl-propan-2-ols was designed as new analogs of fluconazole (FLC) by replacing one of its two triazole moieties by an indole scaffold. Two different chemical approaches were then developed. The first one, in seven steps, involved the synthesis of the key intermediate 1-(1H-benzotriazol-1-yl)methyl-1H-indole and the final opening of oxiranes by imidazole or 1H-1,2,4-triazole. The second route allowed access to the target compounds in only three steps, this time with the ring opening by indole and analogs. Twenty azole derivatives were tested against Candida albicans and other Candida species. The enantiomers of the best anti-Candida compound, 2-(2,4-dichlorophenyl)-3-(1H-indol-1-yl)-1-(1H-1,2,4-triazol-1-yl)-propan-2-ol (8g), were analyzed by X-ray diffraction to determine their absolute configuration. The (−)-8g enantiomer (Minimum inhibitory concentration (MIC) = IC80 = 0.000256 µg/mL on C. albicans CA98001) was found with the S-absolute configuration. In contrast the (+)-8g enantiomer was found with the R-absolute configuration (MIC = 0.023 µg/mL on C. albicans CA98001). By comparison, the MIC value for FLC was determined as 0.020 µg/mL for the same clinical isolate. Additionally, molecular docking calculations and molecular dynamics simulations were carried out using a crystal structure of Candida albicans lanosterol 14α-demethylase (CaCYP51). The (−)-(S)-8g enantiomer aligned with the positioning of posaconazole within both the heme and access channel binding sites, which was consistent with its biological results. All target compounds have been also studied against human fetal lung fibroblast (MRC-5) cells. Finally, the selectivity of four compounds on a panel of human P450-dependent enzymes (CYP19, CYP17, CYP26A1, CYP11B1, and CYP11B2) was investigated.

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Section: Resultsmentioning

confidence: 99%

Synthesis, Optimization, Antifungal Activity, Selectivity, and CYP51 Binding of New 2-Aryl-3-azolyl-1-indolyl-propan-2-ols

Lebouvier

Pagniez

et al. 2020

Pharmaceuticals

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“…The other ring systems used in the design of the series of DASIs discussed herein have been previously incorporated in either AIs (benzofuran), STS inhibitors (benzoxazoles), or both (indoles). For the latter series, this is exemplified by a range of novel aromatase inhibitors based on 2‐, 3‐, 4‐, 5‐, 6‐, or 7‐[(aryl)(azolyl)methyl]‐1 H ‐indole systems,40–43 from which the most potent compound is 4‐[(1 H ‐imidazol‐1‐yl)(1 H ‐indol‐4‐yl)methyl]benzonitrile, with an IC 50 value of 11.5 n M when evaluated in a microsomal preparation of human placental tissue 43. The potency of the two indole‐containing derivatives described herein ( 45 and 52 ) against aromatase is similar, with IC 50 values in the low nanomolar range (IC 50 AROM =2.7 and 2.3 n M , respectively).…”

Section: Biological Results and Discussionmentioning

confidence: 99%

A protocol to remove colored metabolites and other inhibitors from plant tissues to facilitate RNA isolation suitable for downstream applications

Singh

Kumar

2012

Biotechnology Progress

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This work developed a protocol to remove colored metabolites and other interfering substances to facilitate RNA isolation. These metabolites otherwise hinder RNA isolation and downstream applications. The developed protocol used sodium dodecyl sulphate, ethylenediamine tetra-acetic acid, and ethanol in a definite ratio that removed the said metabolites from the tissue and aided isolation of RNA using the existing methods. The protocol was developed for red colored roots of Arnebia euchroma and was extended to other colored tissues [rhizome of Rheum australe (Himalayan Rhubarb) and taproot of Daucus carota (purple carrot)] with success. Without inclusion of our protocol, the existing methods could not isolate good quality RNA from these tissues. RNA isolated by the developed protocol had A(260/280) ratio of 1.88-1.93, A(260/230) ratio of 1.94-2.0, and RNA integrity number of 6.3-8.0. RNA was amenable to downstream applications such as reverse-transcription polymerase chain reaction and primer extension assay.

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“…14 Some indole derivatives such as azolylmethyl-1 H -indoles, 15–18 azolylbenzyl-1 H -indoles, 15, 19, 20 5-aryl(imidazol-1-yl)methyl-1 H -indoles, 21 6- and 4-aroylindoles, 22 indole-3-carbinols, 23 indole-imidazoles, 24 and 2- and 3-aryl(azolyl)methylindoles 25 have been previously synthesized and evaluated as potential anti-aromatase agents. Recently, Cushman and coworkers developed a series of resveratrol analogs by replacing the trans double bond with a thiadiazole moiety and discovered a promising new compound with dual activity against aromatase and QR1 (Figure 2).…”

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confidence: 99%

Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1

Prior

Park

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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In our ongoing effort of discovering anticancer and chemopreventive agents, a series of 2-arylindole derivatives were synthesized and evaluated toward aromatase and quinone reductase 1 (QR1). Biological evaluation revealed that several compounds (e.g., 2d, IC50 = 1.61 μM; 21, IC50 = 3.05 μM; and 27, IC50 = 3.34 μM) showed aromatase inhibitory activity with half maximal inhibitory concentration (IC50) values in the low micromolar concentrations. With regard to the QR1 induction activity, 11 exhibited the highest QR1 induction ratio (IR) with a low concentration to double activity (CD) value (IR = 8.34, CD = 2.75 μM), while 7 showed the most potent CD value of 1.12 μM. A dual acting compound 24 showed aromatase inhibition (IC50 = 9.00 μM) as well as QR1 induction (CD = 5.76 μM) activities. Computational docking studies using CDOCKER (Discovery Studio 3.5) provided insight in regard to the potential binding modes of 2-arylindoles within the aromatase active site. Predominantly, the 2-arylindoles preferred binding with the 2-aryl group toward a small hydrophobic pocket within the active site. The C-5 electron withdrawing group on indole was predicted to have an important role and formed a hydrogen bond with Ser478 (OH). Alternatively, meta-pyridyl analogs may orient with the pyridyl 3′-nitrogen coordinating with the heme group.

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Synthesis of 6- or 4-functionalized indoles via a reductive cyclization approach and evaluation as aromatase inhibitors

Cited by 35 publications

References 23 publications

Synthesis, Optimization, Antifungal Activity, Selectivity, and CYP51 Binding of New 2-Aryl-3-azolyl-1-indolyl-propan-2-ols

Synthesis, Optimization, Antifungal Activity, Selectivity, and CYP51 Binding of New 2-Aryl-3-azolyl-1-indolyl-propan-2-ols

A protocol to remove colored metabolites and other inhibitors from plant tissues to facilitate RNA isolation suitable for downstream applications

Structure-activity relationships and docking studies of synthetic 2-arylindole derivatives determined with aromatase and quinone reductase 1

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