Triphenylethylene

Triphenylethylene has been prepared by the reaction of phenylmagnesium bromide with benzyl benzoate, with desoxy-benzoin, or with ethyl pheaniylacetate, and by the reaction of diphenylketene-quinoline with benzaldehyde. The above procedure is an adaptation of that described by Hell and Wiegandt. ... 

Dulou et al. (66) have assigned the trans configuration to the pyrrolidine examine of desoxybenzoin (133) on the basis of the comparison of its UV SDectrum with that of tran -stilbene and triphenylethylene. This assignment is open to question in the light of the work of Munk and Kim (63). 

The reaction of benzylmagnesium chlorides wnth thiophenealde-hydes and thienyl ketones has been used for the preparation of styrylthiophenes and 1,2,2-triarylethylenes, which are of biological interest. In stilbene and 1,2,2-triphenylethylene the reactivity toward electrophilic reagents is transferred with deactivation to the double bond. However, styrylthiophene is formylated and acylated... 

The effect of substrate structure on product profile is further illustrated by the reactions of cis- and trons-stilbene oxides 79 and 83 with lithium diethylamide (Scheme 5.17) [32]. Lithiated cis-stilbene oxide 80 rearranges to enolate 81, which gives ketone 82 after protic workup, whereas with lithiated trans-stilbene oxide 84, phenyl group migration results in enolate 85 and hence aldehyde 86 on workup. Triphenylethylene oxide 87 underwent efficient isomerization to ketone 90 [32]. 

Selective estrogen receptor modulators (SERMs) are synthetic compounds with partially agonistic and partially antagonistic estrogenic properties. In bone, SERMs inhibit bone resorption via the mechanisms known for estrogens. Major SERMs are tamoxifen, a triphenylethylene compound, and raloxifene. In postmenopausal women, the latter has been shown to prevent bone loss and to reduce fracture risk by 40%. 

The quantum-mechanical treatment previously applied to benzene, naphthalene, and the hydrocarbon free radicals is used in the calculation of extra resonance energy of conjugation in systems of double bonds, the dihydro-naphthalenes and dihydroanthracenes, phenylethylene, stilbene, isostilbene, triphenylethylene, tetraphenylethyl-... 

The secular equation for triphenylethylene, corresponding to 8, 36, 36, and 36 structures of the four kinds described for stilbene, is... 

The synthetic method leading to Nb-alkylidenes and Nb-alkylidynes was particularly successful, due to a quite remarkable difference in the reaction rate of 29 with ketones or aldehydes, vs the subsequent reaction of the alkylidene with ketones and aldehydes (see Scheme 37). The former reaction takes a few minutes at -40°C, while the latter one occurs in hours at room temperature.88 The reaction between 178 and benzaldehyde led to triphenylethylene and the niobyl derivative 184. Due to the difference in reaction rates between a and b in Scheme 37, it was found that the sequential addition of two different ketones or aldehydes to a THF solution of 29 produced a nonsymmetric olefin in a stepwise McMurry-type reaction.84 This is exemplified in the coupling shown in reaction c (Scheme 37). The proposed reaction pathway does not involve the intermediacy of a pinacolato ligand and therefore differs from the mechanism of the McMurry reaction and related reductive couplings at activated metal sites.89... 

It is difficult to see why the spectra of the ions from diphenylethylene and triphenylethylene should resemble that of the ion from anthracene if the ions have the non-classical protonated double bond structure. 

Triphenylethylenes Tamoxifen Clomifene Toremifene Droloxifene Miproxifene (TAT-59) Idoxifene Ospemifene (FC- la)1 Fispemifene GW5638 MDL 103,323 AstraZeneca Orion Pfizer Taiho Pharm SmithKline Beecham Hormos Medical Corp Hormos Medical Corp Duke University Hoechst-Marion-Roussel... 

Fig. 2.1. Chemical structure of several SERMs in triphenylethylene group. The estradiol molecule is also included as a comparative reference...

Miproxifene (TAT-59) is a prodrug of 4-hydroxy-tamoxifen that has been developed for tamoxifen-resistant carcinoma, but relatively little information has been published on this drug. Compared with tamoxifen, miproxifene inhibits estradiol-stimulated proliferation of MCF-7 cells at a threefold lower dose than that of tamoxifen, and of dimethyl-benzanthracene (DMBA)-induced rat mammary tumors at a dose tenfold lower than tamoxifen (Toko et al. 1990). In any event, in preclinical castrated rat models, it shows an endometrial stimulation activity that is similar to that of tamoxifen, which means it has limited potential use in the prevention or treatment of osteoporosis or cardiovascular disease (Shibata et al. 2000). Similarly, considering the preclinical findings of endometrial stimulation reported on GW5638 (Willson et al. 1997), it is likely that this new SERM belonging to the triphenylethylene family will be limited in clinical use to the treatment of advanced tamoxifen-resistant breast cancer once its efficacy is demonstrated in human clinical trials. 

Qu Q, Zheng H, Dahllund J, Laine A, Cockcroft N, Peng Z, et al. (2000) Selective estrogen effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact ovariectomized rats. Endocrinology 141 809-820... 

Electrophysiological studies on primary cultures of hypothalamic neurons and C1300 neuroblastoma cells have shown that the triphenylethylene SERMs ta-... 

Fig. 4.2. Effects of triphenylethylene SERMs on spontaneous and depolarization-induced contractions in visceral smooth muscle. Tamoxifen (a) and ethylbromide tamoxifen (EBTx, b) rapidly and reversibly inhibit spontaneous peristaltic activity in duodenal muscle. Both compounds also inhibit depolarization-induced tonic contraction of uterine muscle (c). The inhibition of L-type voltage-dependent calcium channels underlies the relaxing effects illustrated here. Drugs concentrations were 10 xM in all cases. %RA percent of activity related to maximal activity...

Volume-sensitive chloride channels are also sensitive to triphenylethylene SERMs. Thus, tamoxifen, 4-OH-tamoxifen, and toremifene were all found to... 

The use of triphenylethylene SERMs as Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration, which is likely due to the involvement of proteins with the ability to bind these compounds. For instance, toremifene is able to reverse MDR and to sensitize human renal cancer cells to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular a 1-acid glycoprotein (AAG), which may limit its tissue availability (Braybrooke et al. 2000). In agreement with this, Chatterjee and Harris (1990) have shown that tamoxifen and 4-OH-tamoxifen were similarly potent in reversing MDR in Chinese hamster ovary (CHO) cells with acquired resistance to adriamycin. However, the addition of AAG (0.5 to 2 mg/ml, the range found in vivo) to cell cultures decreased the effect of tamoxifen on reversing MDR, and at the highest AAG concentration there was a complete reversal of the effects of... 

Nonsteroidal SERMs can also amplify signal-induced Ca2+ surges by inhibiting Ca2+-calmodulin-dependent membrane (Ca2+ + Mg2+)-ATPase. For instance, in synaptic plasma membranes and red cell membrane ghosts, tamoxifen and other triphenylethylene compounds (but not estradiol) have been... 

Dfaz M, Bahamonde MI, Lock H, Munoz F, Hardy SP, Posas F, Valverde MA (2001) Okadaic acid-sensitive activation of Maxi Cl" channels by triphenylethylene antiestrogens in C1300 neuroblastoma cells. J Physiol 536(l) 79-88... 

Dfaz M (2002) Triphenylethylene antiestrogen-induced acute relaxation of mouse duodenal muscle. Possible involvement of calcium channels. Eur J Pharmacol 445 257-266... 

Marrero-Alonso J, Garcia Marrero B, Gomez T, Diaz M (2005) Functional inhibition of intestinal and uterine muscles by non-permeant triphenylethylene derivatives. Eur J Pharmacol (in press)... 

O Brian CA, Ward NE, Anderson BW (1988) Role of specific interactions between protein kinase C and triphenylethylenes in inhibition of the enzyme. J Natl Cancer Inst... 

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