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At least 253 records · Page 14Linked to original sources
PubMed1996

Dissociation of 4-hydroxytamoxifen, but not estradiol or tamoxifen aziridine, from the estrogen receptor as the receptor binds estrogen response element DNA.

Estradiol-liganded estrogen receptor (E2-ER) binds EREs with a stoichiometry of one E2-ER dimer per estrogen response element (ERE). In contrast, although 4-hydroxytamoxifen (4-OHT)-liganded ER (4-OHT-ER) binds EREs with high affinity, its saturation ERE binding capacity is consistently half that of E2-ER, giving an apparent stoichiometry of one 4-OHT-ER monomer per ERE. Here we show that one molecule of 4-OHT ligand dissociates from the ER dimer apparently during the process of binding to DNA. Under equilibrium conditions, the type I antiestrogen tamoxifen aziridine (TAz), covalently attached to ER (TAz-ER), binds a single ERE with high affinity (Kd = 0.27 nM), comparable to that of E2-ER and 4-OHT-ER. In contrast to 4-OHT-ER, the ERE binding stoichiometry of TAz-ER was identical to that of E2-ER: one dimeric receptor per ERE. By measuring [3H]ligand that was initially bound to ER, a significant loss of [3H]4-OHT from ER was detected after ERE binding, whereas all [3H]E2 or [3H]TAz remained ER-bound. These results confirm that one molecule of 4-OHT ligand dissociates from the ER dimer as a consequence of ERE binding. Binding of 4-OHT and TAz are likely to induce a conformation in ER dimers that alters their capacity for gene activation. Upon ER binding to DNA, this conformation reveals itself by allowing 4-OHT dissociation, and predictably would allow TAz dissociation were it not bound covalently.

Base Sequence↗
PubMed1998

The two native estrogen receptor forms of 8S and 4S present in cytosol from human uterine tissues display opposite reactivities with the antiestrogen tamoxifen aziridine and the estrogen responsive element.

We have investigated the capability of the different native ER forms, present in cytosols from human uterine tissues, of reacting with the antiestrogen [3H]Tamoxifen aziridine ([3H]TA) and with the Estrogen Responsive Element (ERE). Cytosols from uterine leiomyoma (myoma) prepared in buffer containing 40 mM molybdate and protease inhibitors, labelled with [3H]estradiol and analyzed in low-salt sucrose gradient showed 8S and 4S ER forms. The same cytosols labelled with [3H]TA only showed a 4S ER form, whereas the ERE only reacted with fractions from the 8S peak. The band of ERE reaction in the EMSA assay showed a lower relative mobility than the band labelled with [3H]TA, but both bands contained immunoreactive ER of 65 kDa. Electrophoretic mobility of the [3H]TA-labelled band in that system was not affected by cytosol treatment with cross-linkers or SDS, which suggests that it is a monomeric protein. The [3H]TA-binding 4S ER form was found in all studied myoma samples, as well as in human endometrium or myometrium, but not in rat tissues. These results suggest that the 8S and 4S ER form were already present before cytosol from human uterine tissues comes into contact with the molybdate buffer. They both contain the same ER molecule of 65 kDa, either in the free form or as an oligomer. Only the ER dimers, which have been described both in the cytosolic 8S form and in the nuclear 4-5S form, react with the ERE. [3H]TA only binds to the 4S ER monomer probably because its binding site is concealed in the 8S form under these experimental conditions. The opposite reactivity of the 8S and 4S ER forms with [3H]TA and the ERE support the hypothesis that they may constitute separate entities with a different physiological role.

Animals↗
PubMed1998

4-iodotamoxifen aziridine, a new affinity labeling agent for the rapid detection of estrogen receptor isoforms.

We describe the simple and fast preparation of a new radioiodinated probe for the detection of the estrogen receptor (ER) and its isoforms. Iodotamoxifen aziridine was labeled with iodine 125 ([125I]TAZ) in position 4 of the alpha aromatic ring. The yield was high (>75%), the label was stable and the specific activity was near optimal (1900-2170 Ci/mmol). The apparent relative binding affinity of the probe to a recombinant human ER (hER) was high (RBA = 35 vs estradiol = 100). Electrophoretic studies (SDS-PAGE) with this hER indicated the high potency of [125I]TAZ at very low concentration (<1 nM) to reveal ER bands after a short exposure time (1-4 days). Competition between this probe and various compounds as well as chemical treatments of the ER with SH-reactive chemicals, demonstrated the labeling specificity. Analysis of cytosols from a panel of cell lines and various rat reproductive organs displayed characteristic ER bands (67, 50 and 37 kDa) suppressed by unlabeled E2. Detection in nonreproductive organs of 43 kDa E2-nondisplaceable peptide raised the question upon the presence of altered and/or variant ERs in many tissues. Data concerning human breast cancer cytosols were in complete accordance with those established with [3H]TAZ: high ER polymorphism in most ER-positive samples and peculiar forms (mainly 43 kDa) in ER-negative samples. Hence, [125I]TAZ appears especially useful for the detection of altered ER or related peptides in breast cancers.

Affinity Labels↗
PubMed2004

Cu(I) beta-diketiminates for alkene aziridination: reversible Cu-arene binding and catalytic nitrene transfer from PhI=NTs.

beta-Diketiminato Cu(I)-lutidine complexes [RMeNN]Cu(2,4-lutidine) (R = Me (4a), (i)Pr (4b)) were prepared in high yield from Tl[RMeNN] and [CuBr(2,4-lutidine)(2)](2). Both 4a and 4b reversibly dissociate lutidine base in toluene to give [RMeNN]Cu(toluene) solvento complexes. A related base-free dicopper species [[Me(2)NN]Cu](2) (6) bridged via eta(2)-binding of opposing N-aryl rings could be isolated by the addition of Tl[Me(2)NN] to CuBr. The lutidine precursors serve as precatalysts for the aziridination of alkenes with PhI=NTs. Styrene, beta-methylstyrene, and cyclooctene gave the highest yields (59-96%) with a low olefin to PhI=NTs ratio (3:1) and 5 mol % catalyst loading.

Journal Article↗
PubMed2002

The effect of HMPA on the reactivity of epoxides, aziridines, and alkyl halides with organolithium reagents.

A kinetic study of the effect of added HMPA cosolvent on the reaction of 2-lithio-1,3-dithiane (1), bis(phenylthio)methyllithium (2), and bis(3,5-bistrifluoromethylphenylthio)methyllithium (3) with methyloxirane (propylene oxide), N-tosyl-2-methylaziridine, and the several alkyl halides (BuCl, BuBr, BuI, allyl chloride) was carried out. Widely varied rate effects of HMPA on these SN2 substitutions were observed, ranging from >108 rate increases for 1 and butyl chloride to >103 rate decreases for 3 and methyloxirane. These reactions appear to go through separated ion pair intermediates, so a key effect is the ease of ion pair separation of the lithium reagent (3 > 2 > 1). Because 3 is already almost fully separated in THF, HMPA has no effect on the rate of halide substitution, but a large reduction is observed with the epoxide as substrate, a consequence of strong lithium assistance to the ring opening which is suppressed when excess HMPA is present. When ion pair separation is difficult (1), modest rate increases (104) are seen for epoxide opening, but very large increases are seen for aziridine (106) and alkyl halide reactions (108), for which lithium assistance is much less important. Reagent 2 shows more complicated behavior in reaction with the epoxide: 1-2 equiv of HMPA causes a small rate increase, while larger amounts cause a large rate decrease. Here the rate-accelerating effects of SIP formation are more nearly balanced with the rate-retarding effects of suppression of lithium catalysis.

Journal Article↗
PubMed2004

Lewis acid-promoted carbon-carbon bond cleavage of aziridines: divergent cycloaddition pathways of the derived ylides.

Lewis acids are shown to cleave the carbon-carbon bond of activated aziridines at ambient temperature. The derived metal-coordinated azomethine ylides undergo cycloaddition reactions with electron-rich alkenes. Cyclic alkenes afford products that are formally [4+2] adducts most likely derived from a Mannich-type addition to the ylide, followed by intramolecular Friedel-Crafts alkylation. Alternatively, acyclic alkenes undergo [3+2] cycloaddition to give new pyrrolidine products.

Journal Article↗
PubMed2005

Palladium pincer complex catalyzed substitution of vinyl cyclopropanes, vinyl aziridines, and allyl acetates with tetrahydroxydiboron. An efficient route to functionalized allylboronic acids and potassium trifluoro(allyl)borates.

Palladium-catalyzed boronation of vinyl cyclopropane, vinyl aziridine, and allyl acetate substrates could be accomplished using tetrahydroxydiboron reagent in the presence of SeCSe pincer complex catalyst 1a. These reactions result in allyl boronic acids, which were converted to synthetically useful trifluoro(allyl)borates or allyl boronates. The catalytic transformations proceed under mild and neutral conditions, and therefore many functionalities Br, COOEt, ArSO2(NH), OAc, and SiRMe2 are tolerated. The selectivity of the presented processes is very high, affording the linear products incorporating a trans double bond.

Journal Article↗
PubMed2001

The first synthesis of enantiopure alpha-amino ketimines and amino aziridines.

Chiral 1-aminoalkyl chloromethyl ketimines 2 are synthesized in enantiomerically pure form starting from 1-aminoalkyl chloromethyl ketones 1 and different amines. Reduction of amino ketimines 2 and subsequent spontaneous cyclization affords aminoalkyl aziridines 3 with high diastereoisomeric excess and without detectable racemization.

Journal Article↗
PubMed2002

Highly diastereoselective aziridination of imines with trimethylsilyldiazomethane. Subsequent silyl substitution with electrophiles, ring opening, and metalation of C-silylaziridines--a cornucopia of highly selective transformations.

Treatment of a range of N-sulfonyl (Ts and SES) imines derived from aromatic, heteroaromatic, aliphatic, and unsaturated aldehydes with trimethylsilydiazomethane gave C-silylaziridines in good yield (32-83%) and with high diastereoselectivity in favor of the cis product (80:20-100:0). In contrast, an alpha-imino ester gave predominantly the trans-aziridine (89:11) in high yield (91%). The synthetic potential of C-silylaziridines was investigated. Treatment with F(-) (tetrabutylammonium triphenyldifluorosilicate was used) in the presence of aldehydes gave the alpha-hydroxyaziridines in high yield and high diastereoselectivity (86:14-98:2) for the newly created stereogenic center. Complete retention of configuration was observed in the substitution of the silyl group with electrophiles in all cases. Trapping with deuterium (using CDCl(3) as electrophile) was also successful, but trapping with phosphate [using ClP(O)(OPh)(2)] and acetate (using Ac(2)O) was unsuccessful. In these latter cases ring opening by chloride and acetate, respectively, was observed. Further ring-opening reactions were effected using azide and thiolate nucleophiles and in all cases complete regioselectivity in favor of attack at the silyl-bearing carbon occurred. Complete regioselectivity was also observed in the carbonylative ring expansion using Co(2)(CO)(8) to give a beta-lactam. Treatment of cis-1-tosyl-2-phenyl/butyl-3-trimethylsilylaziridines with n-BuLi and subsequent quenching with MeI followed completely different pathways, depending on the 2-substituent. In the case of the 2-phenylaziridine, metalation was initiated alpha to the phenyl group and led finally to a fused tricyclic adduct with four stereogenic centers as a single diastereoisomer. In the case of the 2-butylaziridine, metalation occurred alpha to the silyl group and led to a trisubstituted silylaziridine, probably via an azirine intermediate.

Journal Article↗
PubMed2003

Novel stereoselective synthesis of functionalized oxazolidinones from chiral aziridines.

Enantiomerically pure N-(R)-alpha-methylbenzyl-4(R)-(chloromethyl)oxazolidinones (4R)-5a-k were synthesized in one step and high yields from various aziridine-2-methanols (S)-2a-k by intramolecular cyclization with phosgene. The alpha-methylbenzyl substituent on the nitrogen was easily cleaved to give both enanatiomers of 4-(chloromethyl)oxazolidinones (R)-7a and (S)-7a. (R)-7a was used for the efficient syntheses of (L)-homophenylalaninol analogues (S)-12a-j. We also applied the same methodology to prepare oxazolidinones 9a-c containing a heteroatom-substituted alkyl group at C-4 in high yields.

Journal Article↗
PubMed2004

Carbonylative ring expansion of aziridines to beta-lactams with rhodium-complexed dendrimers on a resin.

Rhodium-complexed dendrimers, supported on a resin, were evaluated as catalysts for the carbonylative ring expansion reactions of a variety of aziridines with carbon monoxide to give beta-lactams. The effects of reaction temperature, solvent, time, and pressure of carbon monoxide on this transformation were also investigated. The dendritic catalysts showed comparable activity to the homogeneous analogue. More importantly, this catalytic system can be easily recovered by simple filtration and recycled without significant loss of activity.

Journal Article↗
PubMed2003

Monomeric rhodium(II) catalysts for the preparation of aziridines and enantioselective formation of cyclopropanes from ethyl diazoacetate at room temperature.

A family of bis(oxazoline) complexes of coordinatively unsaturated monomeric rhodium(II) (2a,b, 3a,b) are described. These complexes serve as catalysts for cyclopropanation of olefins by ethyl diazoacetate, giving excellent yields (66-94%). Enantioselectivities for the cis product isomers are good (61-84%). The reaction shows an unusual preference for formation of the cis isomers. Catalytic aziridination of N-aryl imines with ethyl diazoacetate is also described.

Journal Article↗