2-Phenylindoles. Effect of N-benzylation on estrogen receptor affinity, estrogenic properties, and mammary tumor inhibiting activity

Angerer, E. von; Strohmeier, Julian

doi:10.1021/jm00384a022

Cited by 52 publications

(18 citation statements)

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“…None of the compounds showed full agonist activity; all were mixed agonist/antagonists of modest potency, consistent with the behavior of other N -substituted-2-phenylindoles 10-17. They also showed only limited selectivities for ERα and ERor β (data not shown).…”

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confidence: 68%

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Tethered indoles as functionalizable ligands for the estrogen receptor

Trogden

Kim

Lee

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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To create ligands for the estrogen receptor that contain pendant groups for tethering to a poly(amido) amine (PAMAM) dendrimer, we have explored a class of N-substituted 2-phenyl indoles. Attachment of tethers of different length and chemical nature to this non-steroidal indole scaffold gave high affinity ligand-tether conjugates that can be easily functionalized. To further explore the utility of this system, an indole-conjugated dendrimer was prepared and evaluated as an estrogen receptor ligand.The estrogen receptor (ER) is a member of the nuclear hormone receptor superfamily of ligandregulated transcription factors. The ER is regulated primarily by the endogenous estrogen, estradiol (E2, Figure 1), but it is also the target of pharmaceutical agents, including estrogen agonists, antagonists, and selective estrogen receptor modulators (SERMs) that activate the subtypes ERα and ERβ. 1 The binding of E2 or other agonists to ER results in conformational changes that affect its ability to recruit coactivators or corepressors and controls ER interaction with DNA-regulatory sequences, termed estrogen response elements. 2In addition to its nuclear role to regulate gene transcription, ER can also have non-genomic actions by directly activating kinase cascades. These non-genomic effects are more rapid than the transcriptional ones and are mediated through ER from membrane or other extranuclear sites, where it acts as a classical activator of signal transduction. 3 Extranuclear ER is most likely the same protein as nuclear ER, yet it represents only a few percent of total cellular ER, so rigorous characterization of membrane ER has been difficult.Estrogens conjugated to poly(amido)amine (PAMAM) dendrimers have been used to study the non-genomic, extranuclear effects of the estrogen receptor. 4,5 We have found that when an estrogen is conjugated to the highly charged, abiotic PAMAM macromolecule, this estrogen-dendrimer conjugate remains outside of the nucleus, allowing the ligand to activate signaling of only non-nuclear, non-genomic pathways.PAMAMs are available in a number of generations that correspond to progressively increasing molecular weights and surface functionalities. PAMAMs contain multiple surface amine substituents onto which ligands can be covalently attached. Generation-6 PAMAM has a nominal molecular weight of 58 kDa, similar to bovine serum albumin, which has been used as an estradiol carrier 6 ; the dendrimer also has nominally 256 surface primary amines. A distinct advantage of a PAMAM over a protein as a macromolecule for hormone conjugation is that the PAMAM can withstand organic solvents and extraction protocols needed to remove any remaining free ligand, which can confound biological experiments. 4-6 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptProduction of ER ligand-macromolecule conjugates involves four design steps: (I) identifying a good ligand scaffold with a position for covalent attachment of the tether, (II) determining an optimal tether length and ch...

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confidence: 68%

“…1). Many members of this class have pharmacological activity,10-18 and attachment of alkyl groups to the indole nitrogen generally provided favorable ER binding 10,17. The 2-phenylindole estrogens have been tested as inhibitors of mammary tumor growth15 and have been successfully attached to pendant chemotherapy agents to target ER + tumors 11…”

mentioning

confidence: 99%

Tethered indoles as functionalizable ligands for the estrogen receptor

Trogden

Kim

Lee

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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“…Infrared (IR) spectra were recorded on a Thermo Nicolet Nexus FTIR-8700 spectrometer. 1 H-NMR spectra were recorded on a Bruker Avance DMX 400 MHz instrument using TMS as internal standard and CDCl 3 as solvent. HR-MS were carried out with APEX II Bruker 4.7T AS instrument.…”

Section: Methodsmentioning

confidence: 99%

“…N-Arylindoles are known to be important subunits due to their key role in medically biological activities, such as those displaying antiestrogen, 1) analgesic, 2) antimicrobial, 3) neuroleptic, 4) antiallergy, 5) 5-HT 6 receptor antagonists, 6) FTase inhibitors (FTIs), 7) and anti-human immunodeficiency virus (HIV)-1 activities. 8) Although the development of new methodologies for the N-arylation of indoles catalyzed by palladium or copper has received much attention in recent years, [9][10][11][12][13][14] the nucleophilic aromatic substitutions (SNAr) of aryl halides, activated by electron-withdrawing substituents, with indoles represent an alternate route to N-arylindoles for certain substrate combinations.…”

Section: Notesmentioning

confidence: 99%

One-Pot N-Arylation of Indoles Directly from N-Arylsulfonylindoles via Consecutive Deprotection and SNAr Reactions with Activated Aryl Halides

Fan

2009

CHEMICAL & PHARMACEUTICAL BULLETIN

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An efficient one-pot step by step t-BuOK-mediated procedure for the synthesis of N-arylindoles has been developed in moderate to good yields. The protocol involves the consecutive deprotection of N-arylsulfonylindoles as latent indoles and subsequent SNAr reactions with activated aryl halides. This tandem reaction affords an efficient and convenient preparation of N-arylindoles that benefit from prior indoles protection by arylsulfonyl group, and can shorten a reaction sequence and improve synthetic efficiency.

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“…N-Arylindoles are known to be important subunits in a multitude of synthetically and medicinally relevant compounds due to their key role in interestingly biological activities, such as antiestrogen [1], analgesic [2], antiallergy [3], cyclooxygenase (COX)-1 inhibitors [4], neuroleptic [5], 5-HT 6 receptor antagonists [6], FTase inhibitors (FTIs) [7], and anti HIV-1 activities [8]. Usually the Ullmann-type coupling of indoles with aryl halides represents a straightforward and inexpensive approach to N-arylindoles.…”

Section: Introductionmentioning

confidence: 99%

Advances on N-Arylation of Indoles by Cross-Coupling Reactions

Xu¹

2009

MROC

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N-Arylindoles are known to be important subunits due to their key role in medically biological activities. This mini-review initially covers the important advances on the N-arylation of indoles with aryl halides by palladium, copper or other transition metalscatalyzed cross-coupling reactions in recent ten years. Subsequently, the synthesis of N-arylindoles from indoles with aryl halides, activated by electron-withdrawing substituents, by aromatic nucleophilic substitution reactions (SNAr) is also surveyed.As a consequence, this mini-review will initially focus on the important advances on the N-arylation of indoles with aryl halides by palladium, copper or other transition metals-catalyzed crosscoupling reactions in recent ten years (route A). Subsequently, the synthesis of N-arylindoles from indoles with aryl halides, activated by electron-withdrawing substituents, by aromatic nucleophilic substitution reactions (S N Ar) is also investigated (route B). In each subsection, the advances are presented in chronological order to demonstrate sequential progress in this area. 2.An efficient N-arylation of indole with aryl halides in the presence of Cs 2 CO 3 or NaO-t-Bu using DPPF (diphenylphosphinoferrocene)-ligated palladium was reported. N-Arylindoles were obtained in 72-98% yields (Scheme 2). But complete reaction of indole with electron-rich or electron-neutral aryl halides was required the higher temperatures and longer reaction time [13].By choosing an appropriate ligand in combination with Pd 2 (dba) 3 , a wide range of indoles were effectively coupled with a variety of aryl chlorides, bromides, iodides, and triflates to afford the desired coupling products in good yields (Scheme 3) [14].As shown in Scheme 4, by using Pd(OAc) 2 with supporting ligand 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2ylidene (SIPr) . HCl system, less reactive indoles were efficiently coupled with aryl bromides to produce N-arylindoles. The more donating saturated carbene SIPr in combination with an inexpensive Scheme 1.

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2-Phenylindoles. Effect of N-benzylation on estrogen receptor affinity, estrogenic properties, and mammary tumor inhibiting activity

Cited by 52 publications

References 2 publications

Tethered indoles as functionalizable ligands for the estrogen receptor

Tethered indoles as functionalizable ligands for the estrogen receptor

One-Pot N-Arylation of Indoles Directly from N-Arylsulfonylindoles via Consecutive Deprotection and SNAr Reactions with Activated Aryl Halides

Advances on N-Arylation of Indoles by Cross-Coupling Reactions

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