Synthesis and binding affinity to human α and β estrogen receptors of various 7-hydroxycoumarins substituted at 4- and 3,4- positions

Kirkiacharian, S; Lormier, Anh Tuan; Chidiack, Henri; Bouchoux, F.; Cerede, E.

doi:10.1016/j.farmac.2004.08.004

Cited by 19 publications

(12 citation statements)

References 33 publications

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“…Thus, this study highlights the importance of linker development in the design of 4OHT caged compounds, as well as in the design of other photocaged compounds, and underscores the importance of analytical method choice for evaluating the formed products. It is notable that a lack of such precise analysis can result in inaccurate interpretation of biological activities in vitro and in vivo as some of the byproduct-like C-4 substituted coumarin compounds are associated with promiscuous activities such as acting as ligands of estrogen receptors, 43 antioxidants, 44 and antiviral agents. 45 …”

Section: Resultsmentioning

confidence: 99%

Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer

Wong¹,

Roberts

Tang

et al. 2017

ACS Chem. Biol.

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The use of coumarin caged molecules has been well documented in numerous photocaging applications including for the spatiotemporal control of Cre-estrogen receptor (Cre-ERT2) recombinase activity. In this article, we report that 4-hydroxytamoxifen (4OHT) caged with coumarin via a conventional ether linkage led to an unexpected photo-Claisen rearrangement which significantly competed with the release of free 4OHT. The basis for this unwanted reaction appears to be related to the coumarin structure and its radical-based mechanism of uncaging, as it did not occur in ortho-nitrobenzyl (ONB) caged 4OHT that was otherwise linked in the same manner. In an effort to perform design optimization, we introduced a self-immolative linker longer than the ether linkage and identified an optimal linker which allowed rapid 4OHT release by both single-photon and two-photon absorption mechanisms. The ability of this construct to actively control Cre-ERT2 mediated gene modifications was investigated in mouse embryonic fibroblasts (MEFs) in which the expression of a green fluorescent protein (GFP) reporter dependent gene recombination was controlled by 4OHT release and measured by confocal fluorescence microscopy and flow cytometry. In summary, we report the implications of this photo-Claisen rearrangement in coumarin caged compounds and demonstrate a rational linker strategy for addressing this unwanted side reaction.

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Section: Resultsmentioning

confidence: 99%

Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer

Wong¹,

Roberts

Tang

et al. 2017

ACS Chem. Biol.

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“…Kirkiacharian et al [19], synthesized a library of estrogen antagonists based on coumarin scaffold with various substitution patterns and their relative binding affinities (RBA) were evaluated for estrogen alpha and beta receptor in Cos cells. Anticancer results showed that compounds substituted at position 3rd and 4th with phenyl group have higher selectivity for ER- α than ER- β .…”

Section: Introductionmentioning

confidence: 99%

Estrogen alpha receptor antagonists for the treatment of breast cancer: a review

Sharma

Kumar

2018

Chemistry Central Journal

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BackgroundCancer is at present one of the leading causes of death in the world. It accounts for 13% of deaths occurred worldwide and is continuously rising, with an estimated million of deaths up to 2030. Due to poor availability of prevention, diagnosis and treatment of breast cancer, the rate of mortality is at alarming level globally. In women, hormone-dependent estrogen receptor positive (ER+) breast cancer making up approximately 75% of all breast cancers. Hence, it has drawn the extensive attention of researchers towards the development of effective drugs for the treatment of hormone-dependent breast cancer. Estrogen, a female sex hormone has a vital role in the initiation and progression of breast malignancy. Therefore, estrogen receptor is the central target for the treatment of breast cancer.ConclusionIn this review, we have studied various classes of antiestrogens that have been designed and synthesized with selective binding for estrogen alpha receptor (ER). Since estrogen receptor α is mainly responsible for the breast cancer initiation and progression, therefore there is need of promising strategies for the design and synthesis of new therapeutic ligands which selectively bind to estrogen alpha receptor and inhibit estrogen dependent proliferative activity.

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“…In comparison to estradiol, 3-phenyl-4-ethyl-7-hydroxycoumarins and 3-(4-hydroxy-phenyl)-4,7-dihydroxycoumarin showed weak RBA and lack of selectivity toward both ERs. Furthermore, substitution with a second phenyl group at position 4 resulted in 3,4-diphenyl-7-hydroxycoumarin showing an increase in RBA to both ERs but with more selectivity for ER than ER [138].…”

Section: Coumarin-based Sermsmentioning

confidence: 99%

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

Musa

Cooperwood²,

Khan³

2008

CMC

489

190

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The coumarin (benzopyran-2-one, or chromen-2-one) ring system, present in natural products (such as the anticoagulant warfarin) that display interesting pharmacological properties, has intrigued chemists and medicinal chemists for decades to explore the natural coumarins or synthetic analogs for their applicability as drugs. Many molecules based on the coumarin ring system have been synthesized utilizing innovative synthetic techniques. The diversity oriented synthetic routes have led to interesting derivatives including the furanocoumarins, pyranocoumarins, and coumarin sulfamates (COUMATES), which have been found to be useful in photochemotherapy, antitumor and anti-HIV therapy, and as stimulants for central nervous system, antibacterials, anti-inflammatory, anti-coagulants, and dyes. Of particular interest in breast cancer chemotherapy, some coumarins and their active metabolite 7-hydroxycoumarin analogs have shown sulfatase and aromatase inhibitory activities. Coumarin based selective estrogen receptor modulators (SERMs) and coumarin-estrogen conjugates have also been described as potential antibreast cancer agents. Since breast cancer is the second leading cause of death in American women behind lung cancer, there is a strong impetus to identify potential new drug treatments for breast cancer. Therefore, the objective of this review is to focus on important coumarin analogs with antibreast cancer activities, highlight their mechanisms of action and structure-activity relationships on selected receptors in breast tissues, and the different methods that have been applied in the construction of these pharmacologically important coumarin analogs.

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Synthesis and binding affinity to human α and β estrogen receptors of various 7-hydroxycoumarins substituted at 4- and 3,4- positions

Cited by 19 publications

References 33 publications

Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer

Control of an Unusual Photo-Claisen Rearrangement in Coumarin Caged Tamoxifen through an Extended Spacer

Estrogen alpha receptor antagonists for the treatment of breast cancer: a review

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

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