Synthesis and relative binding affinity to steroid receptors and antiproliferative activity on MCF-7 cells of 2,3-disubstituted indenes

Kirkiacharian, S; Koutsourakis, P. G.; Philibert, D.; Bouchoux, F.; Velde, P. van de

doi:10.1016/s0014-827x(99)00080-4

Cited by 10 publications

(4 citation statements)

References 22 publications

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“…Compound 48, a plant derived tetracyclic coumarin, bears similar chemical features as estrogen attributed to its apparently crude mimicry of the steroid skeleton, thus making it possible for the coumarin moiety of the molecule to mimic the A/B ring of estrogen. SAR studies of the structure and relative binding affinities (RBAs) of various 3-substituted coumarins revealed that substituents at positions 3 and 7 resulted to an increase in RBA for the ERa [135][136][137]. 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.…”

Section: Coumarin-based Sermsmentioning

confidence: 99%

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

Musa

Cooperwood²,

Khan³

2008

CMC

479

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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Section: Coumarin-based Sermsmentioning

confidence: 99%

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

Musa

Cooperwood²,

Khan³

2008

CMC

479

190

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“…The introduction of an aminoethyl substituent at C-2 of the quinoline nucleus results in strong cytotoxic properties in the compound 56 together with antiestrogenic properties. 2,3-Disubstituted indenes [224] and piperidinediones have also been investigated for antiproliferative effects and estrogen binding activity [225].…”

Section: Diphenyl Quinolines and Isoquinolinesmentioning

confidence: 99%

Advances in the Science of Estrogen Receptor Modulation

Mj¹,

Dg²

2003

CMC

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This work details recent advances in the science of estrogen receptor (ER) modulation, with emphasis on the discovery of novel ligands for the ER ligand binding domain (LBD). A detailed examination of structural studies of the ERs is presented with analysis of the impact of such works on contemporary ligand design and the molecular pharmacology of the ER. The various classes of ER modulators are discussed on the basis of stuctural similarities including selective estrogen receptor modulators (SERMs) and 'pure' non-steroidal antiestrogens. Additionally we review the emergence of a novel selective class of modulator which we have termed the selective estrogen receptor subtype modulators (SERSMs) and, in a departure from LBD strategies we examine the discovery of novel peptide inhibitors of the ER which inhibit transcriptional activiation of agonist liganded receptor through interaction with coactivator recruitment proteins, and offer unique insight to the mechanism of action of all classes of ER modulators. Through examination of patent and classical literature we present a thorough and informative cross-section of the contemporary state of the art in this exciting field of pharmaceutical research.

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“…26 A limited series of basic 2,3-diarylindenes was examined for antifertility properties in rats during the 1960s, 27,28 followed by analysis of the binding orientation and fluorescent properties of the 2,3-diarylindenes 21,[29][30][31][32][33] and limited SAR studies. 34 Recently, basic 2-aryl-3-benzylindenes and -benzylindanes have been investigated for their SERM effects in bone and the cardiovascular system. 35 The currently known SERMs, along with the indene SAR data described above, provided a starting point for synthesis of pathway-specific probes based on the unifying diarylindene structure (Figure 1c).…”

Section: Introductionmentioning

confidence: 99%

“…Limited SAR studies of 1,3-dialkyl-2-arylindenes have highlighted the importance of the C-3 stereochemistry and the phenolic hydroxyls for binding and activity − and demonstrated a preference for an ethyl substituent at the 3-position of the indene ring . A limited series of basic 2,3-diarylindenes was examined for antifertility properties in rats during the 1960s, , followed by analysis of the binding orientation and fluorescent properties of the 2,3-diarylindenes ,− and limited SAR studies …”

Section: Introductionmentioning

confidence: 99%

Differential Response of Estrogen Receptor Subtypes to 1,3-Diarylindene and 2,3-Diarylindene Ligands

et al. 2005

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Estrogen receptors (ERs) control transcription of genes important for normal human development and reproduction. The signaling networks are complex, and there is a need for a molecular level understanding of the roles of receptor subtypes ERalpha and ERbeta in normal physiology and as therapeutic targets. We synthesized two series of ER ligands, based on a common indene scaffold, in an attempt to develop compounds that can selectively modulate ER-mediated transcription. The 3-ethyl-1,2-diarylindenes, utilizing an amide linker for the 1-aryl extension, bind weakly to the ERs. The 2,3-diarylindenes bind with high affinity to the ER subtypes and demonstrate a range of different biological activities, both in transcriptional reporter gene assays and inhibition of estradiol-stimulated proliferation of MCF-7 cells. Several ligands differentiate between ERalpha and ERbeta subtypes at an estrogen response element (ERE), displaying various levels of partial to full agonist activity at ERalpha, while antagonizing estradiol action at ERbeta.

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Synthesis and relative binding affinity to steroid receptors and antiproliferative activity on MCF-7 cells of 2,3-disubstituted indenes

Cited by 10 publications

References 22 publications

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

A Review of Coumarin Derivatives in Pharmacotherapy of Breast Cancer

Advances in the Science of Estrogen Receptor Modulation

Differential Response of Estrogen Receptor Subtypes to 1,3-Diarylindene and 2,3-Diarylindene Ligands

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