Potent aromatase inhibitors and molecular mechanism of inhibitory action

Kang, Hongjun; Xiao, Xingqing; Huang, Chao; Yuan, Yan; Tang, Dongyan; Dai, Xinbin; Zeng, Xianghui

doi:10.1016/j.ejmech.2017.11.057

Cited by 50 publications

(31 citation statements)

References 31 publications

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“…Later, the scalability and the wide applicability of the procedure reported by Sanz, was confirmed by another group by preparing a library of substituted 2‐phenylindoles from 2‐nitrostilbenes on a gram scale. The so prepared indoles were then tested as aromatase inhibitors …”

Section: Use Of Molybdenum Catalysts With Phosphines or Glycols As Rementioning

confidence: 99%

“…The so prepared indoles were then tested as aromatase inhibitors. [194] The conditions reported by Sanz for the Mo-catalyzed reductive cyclization protocol, allowed also to synthesize in very good yield 8H-thieno [2,3-b]indole from 3-(2-nitrophenyl) thiophene, used as scaffold for the synthesis of push-pull chromophores. Worth of note, when the reaction was performed without a catalyst, using P(OEt) 3 as both solvent and reductant (classic Cadogan-Sundberg conditions), side products formed to a relatively large extent.…”

Section: Synthesis Of Five-membered Ring Heterocycles Using Phosphinementioning

confidence: 99%

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Transition Metal Catalyzed Reductive Cyclization Reactions of Nitroarenes and Nitroalkenes

2019

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Nitroarenes are the entry point for the production of most nitrogen‐containing aromatic compounds. Thus, any transformation that leads directly from them to the final product allows saving one or more synthetic steps. This review deals with homogeneously catalyzed reactions leading to the formation of N‐heterocyclic compounds from nitroarenes or nitroalkenes in one pot. Reactions that lead to the intermediate formation of amines are not considered. Carbon monoxide is the most often employed reductant because it allows selective reactions, is cheap, and only produces CO2 as stoichiometric byproduct. However, the difficulty in handling pressurized CO has stimulated in recent years the development of CO‐surrogates, that is molecules able to liberate CO during the reaction. The use of phosphines and diols has also been developed in conjunction with molybdenum catalysts. The review focusses in more detail on the literature in the period 2006–2018, but reference to earlier work is made when necessary to put recent results in a more general context.

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Section: Use Of Molybdenum Catalysts With Phosphines or Glycols As Rementioning

confidence: 99%

Section: Synthesis Of Five-membered Ring Heterocycles Using Phosphinementioning

confidence: 99%

Transition Metal Catalyzed Reductive Cyclization Reactions of Nitroarenes and Nitroalkenes

2019

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“…This is probably because of the strong polar interaction of the inhibitor (substituted at C6 of exemestane) with the Ser478 and Thr310 [5,8,9]. Reversible inhibition is one advantage of the azole compounds, although these strongly interfere with other cytochrome enzymes such as CYP2A6 and CYP3A4 [10].…”

Section: Or 4 Respectively) Present Inmentioning

confidence: 99%

“…To understand the aromatase inhibition (AI) action of the azoles, docking studies have been mostly employed [10][11][12]. A docking study by Suvannang et al, (2011) [11], found that Phe134, Trp224, Thr310, and Val373 amino acid residues have common hydrophobic interactions in all the nonsteroidal aromatase inhibitors (AIs), while other CYP19A1 enzyme-inhibitor interactions change with respect to the inhibitors' shape, chemical constituents, and orientation of inhibitor in enzyme cavity.…”

Section: Or 4 Respectively) Present Inmentioning

confidence: 99%

Towards an Understanding of the Mode of Action of Human Aromatase Activity for Azoles through Quantum Chemical Descriptors-Based Regression and Structure Activity Relationship Modeling Analysis

et al. 2020

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Aromatase is an enzyme member of the cytochrome P450 superfamily coded by the CYP19A1 gene. Its main action is the conversion of androgens into estrogens, transforming androstenedione into estrone and testosterone into estradiol. This enzyme is present in several tissues and it has a key role in the maintenance of the balance of androgens and estrogens, and therefore in the regulation of the endocrine system. With regard to chemical safety and human health, azoles, which are used as agrochemicals and pharmaceuticals, are potential endocrine disruptors due to their agonist or antagonist interactions with the human aromatase enzyme. This theoretical study investigated the active agonist and antagonist properties of “chemical classes of azoles” to determine the relationships of azole interaction with CYP19A1, using stereochemical and electronic properties of the molecules through classification and multilinear regression (MLR) modeling. The antagonist activities for the same substituent on diazoles and triazoles vary with its chemical composition and its position and both heterocyclic systems require aromatic substituents. The triazoles require the spherical shape and diazoles have to be in proper proportion of the branching index and the number of ring systems for the inhibition. Considering the electronic aspects, triazole antagonist activity depends on the electrophilicity index that originates from interelectronic exchange interaction (ωHF) and the LUMO energy ( E LUMO PM 7 ), and the diazole antagonist activity originates from the penultimate orbital ( E HOMONL PM 7 ) of diazoles. The regression models for agonist activity show that it is opposed by the static charges but favored by the delocalized charges on the diazoles and thiazoles. This study proposes that the electron penetration of azoles toward heme group decides the binding behavior and stereochemistry requirement for antagonist activity against CYP19A1 enzyme.

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“…Aromatase enzyme inhibitors are an effective modality of treatment for estrogen‐related breast cancer. It is well known that aromatase mediates and enhances estrogen production, and thus, aromatase inhibition with chemical compounds has been considered to be one of the most effective treatment for estrogen receptor‐positive (ER+) breast cancer (Kang et al, ). It is an enzyme complex, which is based on two protein components and is bound to the endoplasmic reticulum (Simpson et al, , ).…”

Section: Introductionmentioning

confidence: 99%

Steroidal alkaloids efficient aromatase inhibitors with potential for the treatment of postmenopausal breast cancer

et al. 2019

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Plant‐derived natural products are of great interest due to their diversity in modern drug discovery. Sarcococca saligna has been used for the treatment of different diseases. The present study was aimed at isolating phytochemical constituents including Alkaloid‐C (a), Dictyophlebine (b), Sarcovagine‐D (c) and Saracodine (d) Holaphylline (e) from Sarcococca saligna to investigate the anticancer effect of these compounds. These compounds were evaluated for inhibition of aromatase enzyme of breast cancer in assistance by molecular docking simulations to understand molecular interaction between the enzyme and ligands. The IC50 values of compound 1 and 5 were found 138.27 ± 0.01 µl and 12.91 ± 0.01 µl, respectively, and both were found active due to their bulky structures in comparison to the active site of aromatase enzyme. The standard drug exemestane showed potent activity in comparison with the test compounds, having IC50 values of 0.052 ± 0.01 µl. Both compounds showed favorable electrostatic interactions with the active site of aromatase enzyme but the shape and steric bulk of the compounds was the limiting factor in their inhibitory effects. New lead compounds could be generated after extensive modifications guided by computational and experimental tools as a possible anticancer agents by targeting aromatase enzyme.

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Potent aromatase inhibitors and molecular mechanism of inhibitory action

Cited by 50 publications

References 31 publications

Transition Metal Catalyzed Reductive Cyclization Reactions of Nitroarenes and Nitroalkenes

Transition Metal Catalyzed Reductive Cyclization Reactions of Nitroarenes and Nitroalkenes

Towards an Understanding of the Mode of Action of Human Aromatase Activity for Azoles through Quantum Chemical Descriptors-Based Regression and Structure Activity Relationship Modeling Analysis

Steroidal alkaloids efficient aromatase inhibitors with potential for the treatment of postmenopausal breast cancer

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