- Identification of photodegradants of droloxifene by combined HPLC-MS, NMR spectroscopy and computational chemistry
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A combination of high-performance liquid chromatograpny (HPLC)-mass spectrometry and 1H and 13C NMR spectroscopy was utilized to charactorize the photodecay products of droloxifene, a potent new estrogen receptor agonist. Structurally similar to tamoxifen, droloxifene demonstrates a complex and unique decay scheme, including the formation of two naphthalene derivatives which were unexpected decay products and previously unreported for this class of compound. Elucidation of the decay products was assisted by the use of computational chemistry, namely by correlating simulated UV spectra and aqueous solvation free energies with actual UV spectra and HPLC retention data. In addition to describing the photodecay scheme of droloxifene, the present work demonstrates the utility of computational chemistry in providing support for the identification of unknown compounds. Copyright
- Campeta, Anthony M.,Lombardo, Franco,Sharp, Thomas R.,Horan, George J.,Rescek, Diane M.
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- An expeditious synthesis of tamoxifen, a representative SERM (selective estrogen receptor modulator), via the three-component coupling reaction among aromatic aldehyde, cinnamyltrimethylsilane, and β-chlorophenetole
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Two new synthetic pathways to the anti-cancer agent tamoxifen and its derivatives were developed. The first route involved the aldol reaction of benzyl phenyl ketone with acetaldehyde followed by Friedel-Crafts substitution with anisole in the presence of Cl2Si(OTf)2 to produce 1,1,2-triaryl-3-acetoxybutane, a precursor of the tamoxifen derivatives. The second one utilized the novel three-component coupling reaction among aromatic aldehydes, cinnamyltrimethylsilane, and aromatic nucleophiles using HfCl4 as a Lewis acid catalyst to produce 3,4,4-triarylbutene, that is also a valuable intermediate of the tamoxifen derivatives. The former strategy requires a total of 10 steps from the aldol formation to the final conversion to tamoxifen, whereas the latter needs only three or four steps to produce tamoxifen and droloxifene including the installation of the side-chain moiety and the base-induced double-bond migration to form the tetra-substituted olefin structure. This synthetic strategy seems to serve as a new and practical pathway to prepare not only the tamoxifen derivatives but also the other SERMs (selective estrogen receptor modulators) including estrogen-dependent breast cancer and osteoporosis agents.
- Shiina, Isamu,Sano, Yoshiyuki,Nakata, Kenya,Suzuki, Masahiko,Yokoyama, Toshikazu,Sasaki, Akane,Orikasa, Tomoko,Miyamoto, Tomomi,Ikekita, Masahiko,Nagahara, Yukitoshi,Hasome, Yoshimune
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p. 7599 - 7617
(2008/03/14)
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- Short-step synthesis of droloxifene via the three-component coupling reaction among aromatic aldehyde, cinnamyltrimethylsilane, and β-chlorophenetole
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A short-step route for the preparation of droloxifene has been established via the novel three-component coupling reaction among 3-pivaloyloxybenzaldehyde, cinnamyltrimethylsilane, and β-chlorophenetole, the successive installation of the side-chain part, and the base-induced migration of the double bond. The present synthesis of tetra-substituted ethylene moieties is a widely applicable strategy for producing a variety of SERMs (selective estrogen receptor modulators) and SARMs (selective androgen receptor modulators), such as tamoxifen, raloxifene, and other compounds that can lead to new drugs.
- Sano, Yoshiyuki,Shiina, Isamu
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p. 1631 - 1635
(2007/10/03)
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- New highly stereoselective synthesis of (E)-droloxifene via selective protection of 3,4'-dihydroxybenzophenone and McMurry reaction
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A new, highly stereoselective synthesis of (E)-droloxifene is reported. Deprotection of 3,4'-dimethoxybenzophenone and selective pivaloylation of the 3'-phenolic position gave 4-hydroxy-3'-(trimethylacetoxy)benzophenone. A McMurry reaction between the preceding benzophenone and propiophenone gave the (E)-olefin as a major product (14:1 E/Z ratio in crude reaction), which was then alkylated with 2-dimethylaminoethyl chloride and deprotected to yield (E)-droloxifene with a > 100:1 E/Z ratio (5 steps, 13%). Attempts to use this strategy as a suitable stereoselective method to obtain (Z)- droloxifene were not successful. (C) 2000 Elsevier Science Ltd.
- Gauthier, Sylvain,Sancéau, Jean-Yves,Mailhot, Josée,Caron, Brigitte,Cloutier, Julie
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p. 703 - 709
(2007/10/03)
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- Hydroxy derivatives of tamoxifen
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In the exploration of the structural features that affect the RBA (binding affinity for the estrogen receptor of rat uterus relative to that of estradiol) in the tamoxifen [trans-(Z)-1-[4-(dimethylamino)ethoxy]-1,2-diphenyl-1-butene] series, several derivatives variously substituted in the 1-phenyl group have been synthesized. In the tamoxifen series, the descriptors E and Z, which define the configuration of the geometrical isomers and depend on the location and nature of substituents in the aromatic moieties and the ethyl group, may vary, although the relative configuration (cis or trans) does not. In order to avoid confusion the terms cis and trans will be used in this paper to refer to the relative positions of the 4-[2-(dimethylamino)ethoxy]phenyl and ethyl (or hydroxyethyl, hydroxypropyl, or bromo) substituents attached to the ethene moiety]. The final stage of each synthesis involved acid-catalyzed dehydration of a tertiary alcohol, and, in contrast to the known 3- and 4-hydroxy derivatives which were obtained as near-equimolar cis,trans mixtures, only the trans forms of the 2-hydroxy, 2-methyl, 2,4-dihydroxy, and 4-hydroxy-2-methyl derivatives were obtained. Also, in contrast to the trans forms of the 3- and 4-hydroxy derivatives, which are readily equilibrated to cis,trans mixtures, the trans 2-hydroxy derivative could not be isomerized. Tamoxifen and 2-methyltamoxifen had similar RBA's (~1% of that of E2), but that of 2-hydroxytamoxifen was much lower (0.1%). Introduction of a second hydroxyl group (2,4-dihydroxy derivative) enhanced the RBA, and for the 4-hydroxy-2-methyl derivative, the RBA and growth inhibitory activity against the MCF-7 mammary tumor cell line in vitro were high and comparable to those of 4-hydroxytamoxifen, a metabolite of the parent drug. Tamoxifen derivatives hydroxylated at positions 3 or 4 of the 1-butene moiety and the 5-hydroxy-1-pentene analogue were also synthesized, but they had very low RBA values.
- Foster,Jarman,Leung,McCague,Leclercq,Devleeschouwer
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p. 1491 - 1497
(2007/10/02)
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