Investigation of aryl halides as ketone bioisosteres: Refinement of potent and selective inhibitors of human cytochrome P450 19A1 (aromatase)

McNulty, James; Nielsen, Alexander J.; Brown, Carla E.; DiFrancesco, Benjamin R.; Vurgun, Nesrin; Nair, Jerald J.; Crankshaw, Denis; Holloway, Alison C.

doi:10.1016/j.bmcl.2013.09.030

Cited by 7 publications

(6 citation statements)

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“…Notably, the incorporation of an aryl halide resulted in an increase in activity, with all tested compounds demonstrating submicromolar K i and the four most potent compounds ( 41 to 44 ) exhibiting K i ranging from 20 to 70 nM. A molecular docking study confirmed the ability of the triazole to bind to the heme group and suggested that the halide substituents act as ketone bioisosteres, possibly explaining the modest increase in potency over previous compounds 38 to 40 …”

Section: Stilbenes and Stilbenoids As Aismentioning

confidence: 86%

“…Subsequent research in our group explored the effect of halide substitution on the phenyl rings of these 1,2,3‐triazole based AIs (Figure ) . Notably, the incorporation of an aryl halide resulted in an increase in activity, with all tested compounds demonstrating submicromolar K i and the four most potent compounds ( 41 to 44 ) exhibiting K i ranging from 20 to 70 nM.…”

Section: Stilbenes and Stilbenoids As Aismentioning

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: Stilbenes and Stilbenoids As Aismentioning

confidence: 86%

Section: Stilbenes and Stilbenoids As Aismentioning

confidence: 99%

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

Nielsen

McNulty

2018

Medicinal Research Reviews

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“…As discussed earlier, 1,2,3-triazole analogs of aldol products derived from bromine-substituted esters exhibit high inhibition potency against the aromatase enzyme complex (CYP 450 19A1) (Figure ). Therefore, we prepared o - and p -bromine-substituted aldols. Bromine-substituted esters provided 93–96% anti -selectivity in 70–87% yield.…”

Section: Resultsmentioning

confidence: 99%

“…1,2,3-Triazole analogs of 2,3-diaryl-3-hydroxypropanoates, which are prepared from p -bromophenylacetates, exhibit higher enzyme inhibition activity and selectivity than the corresponding compounds derived from unsubstituted phenylacetates (Figure ). In the synthesis of 1,2,3-triazole analogs, an approximately equal mixture of syn - and anti -diastereomers was prepared using lithium bis(trimethylsilyl)amide (LiHMDS)-mediated aldol reactions of arylacetates. However, only one isomer, either syn - or anti -aldol, was found to be useful in preparing a potent inhibitor of the aromatase enzyme complex (CYP 450 19A1).…”

Section: Introductionmentioning

confidence: 99%

Temperature- and Reagent-Controlled ComplementarySyn- andAnti-Selective Enolboration–Aldolization of Substituted Phenylacetates

et al. 2021

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In contrast to methyl phenylacetates, methyl arylacetates do not provide syn-aldols in the dicyclohexylboron triflate/triethylamine (Chx 2 BOTf/Et 3 N)-mediated enolboration− aldolization reaction. However, a combination of a less bulky boron reagent (dibutylboron triflate, n-Bu 2 BOTf), a bulky amine (i-Pr 2 NEt), and ambient temperature is required to obtain syn-aldols from methyl arylacetates. The corresponding anti-aldol products have been synthesized by the enolboration−aldolization of methyl arylacetates in the presence of Chx 2 BOTf/Et 3 N at a lower temperature. We report the first example of a complementary syn-and anti-selective enolboration−aldolization of arylacetates.

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“…133 Aryl halide derivatives of a centrally flexible, five-component 1,2,3-triazole containing moiety ( 55 ) were prepared and evaluated as potential AIs. 134 Among novel indole–imidazole derivatives, 2-(imidazol-1-ylmethyl)-1-[4-(trifluoromethyl)phenyl]indole ( 56 ) was shown to be a highly potent AI. 135 Casimiroin derivatives ( 57 – 59 ) were shown to inhibit both AROM and quinone reductase 2.…”

Section: Recent Advances In the Discovery Of Nonsteroidal Arom Inhmentioning

confidence: 99%

Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure–Function Perspective

Ghosh

Egbuta

2016

J. Med. Chem.

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Human aromatase catalyzes the synthesis of estrogen from androgen with high substrate specificity. For the past 40 years, aromatase has been a target of intense inhibitor discovery research for the prevention and treatment of estrogen-dependent breast cancer. The so-called third generation aromatase inhibitors (AIs) letrozole, anastrozole, and the steroidal exemestane were approved in the U.S. in the late 1990s for estrogen-dependent postmenopausal breast cancer. Efforts to develop better AIs with higher selectivity and lower side effects were handicapped by the lack of an experimental structure of this unique P450. The year 2009 marked the publication of the crystal structure of aromatase purified from human placenta, revealing an androgen-specific active site. The structure has reinvigorated research activities on this fascinating enzyme and served as the catalyst for next generation AI discovery research. Here, we present an account of recent developments in the AI field from the perspective of the enzyme’s structure–function relationships.

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Investigation of aryl halides as ketone bioisosteres: Refinement of potent and selective inhibitors of human cytochrome P450 19A1 (aromatase)

Cited by 7 publications

References 41 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

Temperature- and Reagent-Controlled ComplementarySyn- andAnti-Selective Enolboration–Aldolization of Substituted Phenylacetates

Recent Progress in the Discovery of Next Generation Inhibitors of Aromatase from the Structure–Function Perspective

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