Lead optimization of 4-imidazolylflavans: New promising aromatase inhibitors

Yahiaoui, Samir; Pouget, Christelle; Buxeraud, Jacques; Chulia, Albert J.; Fagnere, Catherine

doi:10.1016/j.ejmech.2011.03.043

Cited by 11 publications

(7 citation statements)

References 24 publications

(29 reference statements)

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“…As well, it was found that a free hydroxy at C7 was more active than a methoxy at the same position. The results from Kellis and Vickery that benzoflavone is a more potent inhibitor of aromatase than flavanone was used as an inspiration for the synthesis of benzoflavone derivatives 109 to 111 , which demonstrated a slight improvement of the activity of 104 and 105 …”

Section: Flavonoids As Aismentioning

confidence: 99%

“…In general, these heterocycles are appended to C2 or C3 of the flavonoid skeleton, or directly replace the C4 carbonyl. Substitution at C3 was first explored by Recanatini et al 77 in 2001, where it was discovered that adding an imidazole ring to C3 of 7-methoxyflavone via a methylene linker resulted in a submicromolar inhibitor of aromatase (86) (Figure 19). Interestingly, exchanging the imidazole group for a 1,3, 4-triazol-1-yl moiety resulted in a compound that was completely inactive (not shown).…”

Section: F I G U R E 1 4 Structure Of Chalcones and Chalconoids And Tmentioning

confidence: 99%

“…The results from Kellis and Vickery 58 that benzoflavone is a more potent inhibitor of aromatase than flavanone was used as an inspiration for the synthesis of benzoflavone derivatives 109 to 111, which demonstrated a slight improvement of the activity of 104 and 105. 86 Besides providing a privileged scaffold for the development of novel AIs, natural flavonoids exhibit other biological activities that may be exploited for the treatment of breast cancer. For example, a diverse set of flavonoids including apigenin, quercetin, genistein, biochanin A, and luteolin have been found to downregulate the expression of aromatase in either human granulosa-luteal cells or MCF-7 cells.…”

Section: F I G U R E 1 4 Structure Of Chalcones and Chalconoids And Tmentioning

confidence: 99%

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Polyphenolic natural products and natural product–inspired steroidal mimics as aromatase inhibitors

Nielsen

McNulty

2018

Medicinal Research Reviews

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The discovery of biologically active polyphenolic natural products, including chalcones, stilbenes, flavanones, and isoflavones as steroidal mimics has proven to be a subject of considerable importance in medicine. Some of these natural compounds have been shown to modulate key human metabolic processes via steroidal hormone receptors, or to inhibit crucial enzymes involved in the biosynthesis of steroidal hormones themselves. Isoflavone polyphenolics such as genistein are well known for this "phytoestrogenic" biological activity. This review focuses on the ability of select polyphenolics and their synthetic derivatives to function as steroidal mimics in the inhibition of the enzyme aromatase, thereby lowering production of endogenous estrogen growth hormones. The discovery of potent, natural product-based aromatase inhibitors (AIs) as hit compounds has led to the introduction of steroidal-based irreversible inhibitors, such as exemestane and reversible AIs such as anastrozole and letrozole, now standard therapy in the treatment of estrogen receptor-positive breast cancer and other hormone related indications. Pursuit of this strategy over the last few decades has been largely successful although complications and challenges remain. This review highlights the aromatase activity of natural stilbenes, chalcones, and flavanones and synthetically inspired versions thereof and draws attention to new and under-investigated areas within each class worthy of pursuit.

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Section: Flavonoids As Aismentioning

confidence: 99%

Section: F I G U R E 1 4 Structure Of Chalcones and Chalconoids And Tmentioning

confidence: 99%

Section: F I G U R E 1 4 Structure Of Chalcones and Chalconoids And Tmentioning

confidence: 99%

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Polyphenolic natural products and natural product–inspired steroidal mimics as aromatase inhibitors

Nielsen

McNulty

2018

Medicinal Research Reviews

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“…As a result, there is a recognized need for next generation inhibitors [23]. A large number of investigators have invested significant effort in the search for novel structures [24][25][26][27] and mechanisms [28][29][30] that bring about adequate aromatase inhibition, while limiting side effects. This search remains active.…”

Section: Introductionmentioning

confidence: 99%

The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents

Pei

et al. 2011

Breast Cancer Res Treat

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To improve the treatment of breast cancer, there has been a need for alternative aromatase inhibitors (AIs) that bring about adequate aromatase inhibition, while limiting side effects. Since two tamoxifen metabolites have been documented as AIs, we tested a wide range of tamoxifen metabolites on aromatase in order to better understand structural interactions with aromatase and constructed structure-function relationships as a first step toward the development of novel inhibitors. The ability of ten tamoxifen metabolites to inhibit recombinant aromatase (CYP19) was tested using microsomal incubations. The selectivity of the most potent aromatase inhibitor identified, norendoxifen, was characterized by studying its ability to inhibit CYP450 enzymes important in clinical drug-drug interactions, including CYP2B6, 2C9, 2C19, 2D6, and 3A. Computerized molecular docking with the X-ray crystallographic structure of aromatase was used to describe the detailed biochemical interactions involved. The inhibitory potency order of the tested compounds was as follows: norendoxifen ≫ 4,4'-dihydroxy-tamoxifen > endoxifen > N-desmethyl-tamoxifen, N-desmethyl-4'-hydroxy-tamoxifen, tamoxifen-N-oxide, 4'-hydroxy-tamoxifen, N-desmethyl-droloxifene > 4-hydroxy-tamoxifen, tamoxifen. Norendoxifen inhibited recombinant aromatase via a competitive mechanism with a K ( i ) of 35 nM. Norendoxifen inhibited placental aromatase with an IC(50) of 90 nM, while it inhibited human liver CYP2C9 and CYP3A with IC(50) values of 990 and 908 nM, respectively. Inhibition of human liver CYP2C19 by norendoxifen appeared even weaker. No substantial inhibition of CYP2B6 and CYP2D6 by norendoxifen was observed. These data suggest that multiple metabolites of tamoxifen may contribute to its action in the treatment of breast cancer via aromatase inhibition. Most of all, norendoxifen may be able to serve as a potent and selective lead compound in the development of improved therapeutic agents. The range of structures tested in this study and their pharmacologic potencies provide a reasonable pharmacophore upon which to build novel AIs.

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“…The degree of LE sorption on MNPs-CS-NIPAM was investigated at various ranges of pH values (3)(4)(5)(6)(7)(8). As shown in Fig.…”

Section: Optimization Of Parametersmentioning

confidence: 99%

Magnetic iron oxide nanoparticles graftedN-isopropylacrylamide/chitosan copolymer for the extraction and determination of letrozole in human biological samples

Moazen

Panahi

2017

J. Sep. Sci.

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Magnetic iron oxide nanoparticles are used for the extraction of a drug from an aqueous solution. In the current study, the magnetic iron oxide nanoparticles were synthesized via a facile coprecipitation approach, and then modified by (3-mercaptopropyl)trimethoxysilane followed by grafting thermosensitive polymer N-isopropylacrylamide and biopolymer chitosan. Structure, morphology, size, thermal resistance, specific surface area, and magnetic properties of the grafted nanosorbent were characterized by using Fourier transform infrared spectroscopy, field emission scanning electron microscopy, transmission electron microscopy, elemental analysis, thermogravimetric analysis, specific surface area analysis and vibrating sample magnetometry. The effective parameters on sorption/desorption of letrozole on grafted magnetic nanosorbent were evaluated. The best sorption of letrozole via the grafted nanosorbent occurred at 20°C at an optimum pH of 7. The extraction of trace letrozole in human biological fluids is investigated and revealed 89.1 and 97.8% recovery in plasma and urine, respectively.

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Lead optimization of 4-imidazolylflavans: New promising aromatase inhibitors

Cited by 11 publications

References 24 publications

Polyphenolic natural products and natural product–inspired steroidal mimics as aromatase inhibitors

Polyphenolic natural products and natural product–inspired steroidal mimics as aromatase inhibitors

The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents

Magnetic iron oxide nanoparticles graftedN-isopropylacrylamide/chitosan copolymer for the extraction and determination of letrozole in human biological samples

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