Studies on Aromatase Inhibitors. II. Synthesis and Biological Evaluation of 1-Amino-1H-1,2,4-triazole Derivatives.

Okada, Minoru; Yoden, Toru; Kawaminami, Eiji; Shimada, Yoshiaki; Kudoh, Masafumi; Isomura, Yasuo

doi:10.1248/cpb.45.333

Cited by 15 publications

(5 citation statements)

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“…An extensive work of structural modification was described, which regarded the azole and benzyl moieties, and at a lesser extent the phenyl substituent. [68][69][70][71] The two compounds selected for in depth evaluation, 15 (IC 50 ¼ 0.12 nM 71 ) and 16 (IC 50 ¼ 0.04 nM 68 ), maintained the quite relevant level of potency that poses them at the top of the list of most active NSAIs known up to date. A good selectivity was also claimed for 15 and 16, evaluated in in vitro cellular assays by testing the inhibition of the synthesis of other steroids (aldosterone, cortisol, testosterone).…”

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confidence: 99%

Nonsteroidal aromatase inhibitors: Recent advances

Recanatini

Cavalli

Valenti

2002

Medicinal Research Reviews

106

102

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Aromatase is the cytochrome P450 enzyme responsible for the last step of estrogen biosynthesis, and aromatase inhibitors constitute an important class of drugs in clinical use for the treatment of breast cancer. Nonsteroidal aromatase inhibitors (NSAIs) are competitive inhibitors of aromatase, which bind to the enzyme active site by coordinating the iron atom present in the heme group of the P450 protein. Presently, third generation NSAIs are in use, and research efforts are being carried out both to identify new molecules of therapeutic interest and to clarify the mechanism of action. In this article, we present a survey of the compounds that have been recently reported as NSAIs, to provide a broad view on the general structure-activity relationships of the class. Moreover, starting from the current knowledge of the mechanistic aspects of aromatase action and from recent theoretical work on the molecular modeling of both enzyme and inhibitors, we try to indicate a way to integrate these different studies in view of a more general understanding of the aromeatase-inhibitor system. Finally, some aspects regarding the possible future development of the field are considered briefly.

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confidence: 99%

Nonsteroidal aromatase inhibitors: Recent advances

Recanatini

Cavalli

Valenti

2002

Medicinal Research Reviews

106

102

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“…A common treatment for estrogen‐dependent cancers is the use of antiestrogens and/or aromatase inhibitors [4]. The usual way to develop new aromatase inhibitors is to screen in vitro chemical compounds [5–10] from the knowledge of the substrate structure, or by comparisons with other aromatases [11–13]. The design of more specific and efficient aromatase inhibitors could be improved by a better knowledge of the enzyme's active site.…”

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confidence: 99%

Study of substrate specificity of human aromatase by site directed mutagenesis

Auvray

Nativelle

Bureau³

et al. 2002

European Journal of Biochemistry

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Human aromatase is responsible for estrogen biosynthesis and is implicated, in particular, in reproduction and estrogen-dependent tumor proliferation. The molecular structure model is largely derived from the X-ray structure of bacterial cytochromes sharing only 15-20% identities with hP-450arom. In the present study, site directed mutagenesis experiments were performed to examine the role of K119, C124, I125, K130, E302, F320, D309, H475, D476, S470, I471 and I474 of aromatase in catalysis and for substrate binding. The catalytic properties of mutants, transfected in 293 cells, were evaluated using androstenedione, testosterone or nor-testosterone as substrates. In addition, inhibition profiles for these mutants with indane or indolizinone derivatives were obtained. Our results, together with computer modeling, show that catalytic properties of mutants vary in accordance with the substrate used, suggesting possible differences in substrates positioning within the active site. In this respect, importance of residues H475, D476 and K130 was discussed. These results allow us to hypothesize that E302 could be involved in the aromatization mechanism with nor-androgens, whereas D309 remains involved in androgen aromatization. This study highlights the flexibility of the substrate-enzyme complex conformation, and thus sheds new light on residues that may be responsible for substrate specificity between species or aromatase isoforms.Keywords: aromatase; site-directed mutagenesis; molecular modeling; androgens; inhibitors.Estrogens are known to be implicated in reproduction and estrogen-dependent tumor proliferation [1]. Moreover, an abnormal expression of aromatase, the enzyme involved in the conversion of androgens to estrogens, has been detected in breast tumors and in surrounding adipose stromal cells [2,3]. The aromatase enzyme comprises a specific cytochrome P-450 aromatase and the ubiquitous cytochrome P-450 NADPH reductase. A common treatment for estrogen-dependent cancers is the use of antiestrogens and/or aromatase inhibitors [4]. The usual way to develop new aromatase inhibitors is to screen in vitro chemical compounds [5][6][7][8][9][10] from the knowledge of the substrate structure, or by comparisons with other aromatases [11][12][13]. The design of more specific and efficient aromatase inhibitors could be improved by a better knowledge of the enzyme's active site. A precise modeling of this part of the molecule is therefore necessary. Despite success in obtaining aromatase purified to homogeneity [14], crystallization of this microsomal membrane-anchored protein has not been reported. Knowledge of the aromatase structure is largely derived from comparisons with soluble bacterial cytochromes Pseudomons putida camphor P-450 (P-450cam), Bacillus megaterium P-450 (P-450BM-3), Pseudomonas putida a-terpineol P-450 (P-450terp) and Saccharopolyspora erythreae erythromycin F P-450 (P-450eryF), these proteins being well characterized and crystallized [15][16][17][18][19]. However, human aromatase shares only 15-20% ...

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“…To efficiently obtain high-affinity aromatase tracers, we considered modifying the structures of known high-affinity aromatase inhibitors YM511 and 4-((4-bromobenzyl)(pyrimidin-5-yl)amino)benzonitrile. , We analyzed binding sites of aromatase and YM511 based on molecular docking and the reported literature studies (Figure ) and three important conclusions were obtained. (1) A parallel π–π interaction was formed between YM511 and the porphyrin in the HEM (Protoporphyrin IX containing Fe).…”

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confidence: 99%

Novel ¹⁸F-Labeled PET Tracers Specific to Aromatase: Design, Synthesis, and Biological Evaluation

et al. 2022

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The abnormal expression of aromatase is associated with the occurrence and development of a variety of neurological diseases and tumors. A series of 18F-labeled and 68Ga-labeled potential aromatase-binding candidate compounds were designed and synthesized based on the structures of aromatase inhibitors. Competitive inhibition experiments in vitro and molecular docking showed that BIBD-069 and BIBD-071 have high affinity for aromatase. The radiolabeling conditions of [18F]BIBD-069 and [18F]BIBD-071 were simple, and the yields were high. Biodistribution and in vivo inhibition experiments confirmed that [18F]BIBD-069 and [18F]BIBD-071 specifically bind to aromatase. [18F]BIBD-069 and [18F]BIBD-071 selectively imaged the amygdala and nucleus of the stria terminalis, which is similar to the imaging result of [11C]vorozole. Radiometabolites of [18F]BIBD-069 and [18F]BIBD-071 did not bind to aromatase and interfered with brain imaging. MicroPET-CT imaging further confirmed that [18F]BIBD-069 and [18F]BIBD-071 can specifically bind to aromatase and were not defluorinated in vivo. Given that [18F]BIBD-069 and [18F]BIBD-071 exhibit excellent aromatase binding affinities, mild radiolabeling conditions, and good pharmacokinetics, they can be important tools for the diagnosis and treatment of aromatase-related diseases.

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Studies on Aromatase Inhibitors. II. Synthesis and Biological Evaluation of 1-Amino-1H-1,2,4-triazole Derivatives.

Cited by 15 publications

References 1 publication

Nonsteroidal aromatase inhibitors: Recent advances

Nonsteroidal aromatase inhibitors: Recent advances

Study of substrate specificity of human aromatase by site directed mutagenesis

Novel ¹⁸F-Labeled PET Tracers Specific to Aromatase: Design, Synthesis, and Biological Evaluation

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Studies on Aromatase Inhibitors. II. Synthesis and Biological Evaluation of 1-Amino-1H-1,2,4-triazole Derivatives.

Cited by 15 publications

References 1 publication

Nonsteroidal aromatase inhibitors: Recent advances

Nonsteroidal aromatase inhibitors: Recent advances

Study of substrate specificity of human aromatase by site directed mutagenesis

Novel 18F-Labeled PET Tracers Specific to Aromatase: Design, Synthesis, and Biological Evaluation

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Product

Resources

About

Novel ¹⁸F-Labeled PET Tracers Specific to Aromatase: Design, Synthesis, and Biological Evaluation