- Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method development for screening of potential tamoxifen-drug/herb interaction via in vitro cytochrome P450 inhibition assay
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Screening for potential drug-drug interaction (DDI) or herb-drug interaction (HDI) using in vitro cytochrome P450 inhibition (IVCI) assays requires robust analytical methods with high sensitivity and reproducibility. Utilization of liquid chromatography-mass spectrometry (LC-MS) for analyte quantification is often hampered by the presence of non-volatile IVCI sample buffer constituents that often results in ion suppression. In this study, to enable screening of drug interactions involving tamoxifen (TAM) metabolism using IVCI-LC-MS/MS, a liquid–liquid extraction (LLE) method was developed and optimized for sample clean-up. Utilization of chloroform as extraction solvent and adjustment of sample pH to 11 was found to result in satisfactory recovery (>70%) and low ion suppression (A LC-MS/MS method was subsequently developed and validated for simultaneous quantification of major TAM metabolites, such as N-desmethyltamoxifen (NDT), endoxifen (EDF) and 4-hydroxytamoxifen (HTF) to enable IVCI sample analysis. Satisfactory separation of E-/Z-isomers of endoxifen with peak resolution (Rs) of 1.9 was achieved. Accuracy and precision of the method was verified within the linear range of 0–50 ng/mL for NDT, 0–25 ng/mL for HTF and 0–25 ng/mL for EDF (E/Z isomers). Inhibitory potency (IC50, Ki and mode of inhibition) of known CYP inhibitors and Strobilanthes crispus extract was then evaluated using the validated method. In summary, the results demonstrated applicability of the developed LLE and validated LC-MS/MS method for in vitro screening of DDI and HDI involving TAM metabolism.
- Liew, Mervyn W. O.,Tan, S. C.,Yaacob, N. S.,Yong, Y. F.
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- New approach based on immunochemical techniques for monitoring of selective estrogen receptor modulators (SERMs) in human urine
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Antiestrogenic compounds such as tamoxifen, toremifen and chlomifen are used illegally by athletes to minimize physical impacts such as gynecomastia resulting from the secondary effects of anabolic androgenic steroids, used to increase athletic efficiency unlawfully. The use of these compounds is banned by the World Anti-Doping Agency (WADA) and controls are made through analytical methodologies such as HPLC–MS/MS, which do not fulfil the sample throughput requirements. Moreover, compounds such as tamoxifen are also used to treat hormone receptor-positive breast cancer (ER +).Therapeutic drug monitoring (TDM) of tamoxifen may also be clinically useful for guiding treatment decisions. An accurate determination of these drugs requires a solid phase extraction of patient serum followed by HPLC–MS/MS. In the context of an unmet need of high-throughput screening (HTS) and quantitative methods for antiestrogenic substances we have approached the development of antibodies and an immunochemical assay for the determination of these antiestrogenic compounds. The strategy applied has taken into consideration that these drugs are metabolized and excreted in urine as the corresponding 4-hydroxylated compounds. A microplate-based ELISA procedure has been developed for the analysis of these metabolites in urine with a LOD of 0.15, 0.16 and 0.63 μg/L for 4OH-tamoxifen, 4OH-toremifen and 4OH-clomifen, respectively, much lower than the MRPL established by WADA (20 μg/L).
- Salvador, J.-Pablo,Vila-Roca, Ester,Monfort, Núria,Ventura, Rosa,Marco, M.-Pilar
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p. 147 - 152
(2018/05/04)
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- Photochemical Activation of Tertiary Amines for Applications in Studying Cell Physiology
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Representative tertiary amines were linked to the 8-cyano-7-hydroxyquinolinyl (CyHQ) photoremovable protecting group (PPG) to create photoactivatable forms suitable for use in studying cell physiology. The photoactivation of tamoxifen and 4-hydroxytamoxifen, which can be used to activate Cre recombinase and CRISPR-Cas9 gene editing, demonstrated that highly efficient release of bioactive molecules could be achieved through one- and two-photon excitation (1PE and 2PE). CyHQ-protected anilines underwent a photoaza-Claisen rearrangement instead of releasing amines. Time-resolved spectroscopic studies revealed that photorelease of the tertiary amines was extremely fast, occurring from a singlet excited state of CyHQ on the 70 ps time scale.
- Asad, Naeem,Deodato, Davide,Lan, Xin,Widegren, Magnus B.,Phillips, David Lee,Du, Lili,Dore, Timothy M.
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supporting information
p. 12591 - 12600
(2017/09/23)
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- Methods for Determining the Oncogenic Condition of Cell, Uses Thereof, and Methods for Treating Cancer
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The invention relates to methods for detecting the oncogenic condition of cells, including step where the amount of the OCDO compound in said cells is measured, and to the uses thereof. The invention further relates to OCDO inhibitors for use in methods for treating cancer.
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- Biomimetic oxidation of aromatic xenobiotics: Synthesis of the phenolic metabolites from the anti-HIV drug efavirenz
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We report the oxidation of the first line anti-HIV drug efavirenz (EFV), mediated by a bio-inspired nonheme Fe-complex. Depending upon the experimental conditions this system can be tuned either to yield the major EFV metabolite, 8-hydroxy-EFV, in enantiomerically pure form or to mimic cytochrome P450 (CYP) activity, yielding 8-hydroxy-EFV and 7-hydroxy-EFV, the two phenolic EFV metabolites reported to be formed in vivo. The successful oxidation of the anti-estrogen tamoxifen and the equine estrogen equilin into their CYP-mediated metabolites supports the general application of bio-inspired nonheme Fe-complexes in mirroring CYP activity.
- Wanke, Riccardo,Novais, David A.,Harjivan, Shrika G.,Marques, M. Matilde,Antunes, Alexandra M. M.
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experimental part
p. 4554 - 4561
(2012/08/08)
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- METHODS FOR DETERMINING THE ONCOGENIC CONDITION OF CELL, USES THEREOF, AND METHODS FOR TREATING CANCER
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The invention relates to methods for detecting the oncogenic condition of cells, including step where the amount of the OCDO compound in said cells is measured, and to the uses thereof. The invention further relates to OCDO inhibitors for use in methods for treating cancer
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- Synthesis of tetrasubstituted alkenes by stereo- and regioselective stannyllithiation of diarylacetylenes
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Addition of trimethylstannyllithium to a diarylacetylene takes place exclusively in an anti-fashion to produce a lithio vinylstannane intermediate. The regioselectivity of the addition is controlled by the steric and electronic property of the acetylene and reaches up to >99:1. The two newly formed C-metal bonds can be sequentially and stereospecifically transformed into two new C-C bonds as illustrated by stereoselective synthesis of 4-hydroxytamoxifen and its regioisomer. A tetraarylethene bearing different aryl groups can be synthesized similarly and cyclized to a substituted dibenzo[g,p]chrysene derivative via a palladium-catalyzed arylation reaction.
- Tsuji, Hayato,Ueda, Yasuyuki,Ilies, Laurean,Nakamura, Eiichi
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supporting information; experimental part
p. 11854 - 11855
(2010/10/19)
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- TARGETED DRUG-FORMALDEHYDE CONJUGATES AND METHODS OF MAKING AND USING THE SAME
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The invention provides a prodrug platform technology for improving the therapeutic value of a variety of parent drug compounds by altering and improving drug characteristics such as aqueous solubility, hydrolytic stability, therapeutic index, toxicity profile, pharmacokinetics and selectivity while allowing the potential for synthetic elaboration. The prodrug platform is particularly well suited for targeting therapeutic drugs, including anti-tumor drugs and antibiotics, to specific receptors on target cells (e.g., cancer cells and bacteria). The platform is a technology for providing an improved, preactivated form of a therapeutic drug, and for optionally targeting such drug to target cells or biological molecules. The invention is broadly applicable to many different therapeutic drugs, as well as to a variety of diseases and conditions, including a variety of forms of cancer and bacterial infections.
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Page/Page column 94
(2008/06/13)
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- Simple and Efficient Production of (Z)-4-Hydroxytamoxifen, a Potent Estrogen Receptor Modulator
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A McMurry coupling reaction and selective crystallization were used to develop a simple and efficient two-step synthesis of (Z)-4-hydroxytamoxifen (2a). This compound is an active metabolite of tamoxifen, a selective estrogen receptor (ER) modulator widely used to treat breast cancer. The synthesis employed 1,1-bis(4-hydroxyphenyl)-2-phenylbut-1-ene (1) as a useful building block.
- Yu, Donna D.,Forman, Barry M.
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p. 9489 - 9491
(2007/10/03)
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- Synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1-butenyl]phenoxyacetic acid
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The synthesis of (Z)-4-hydroxytamoxifen and (Z)-2-[4-[1-(p-hydroxyphenyl)-2-phenyl]-1-butenyl]phenoxyacetic acid was accomplished using a McMurry reaction as the key step. The perfluorotolyl derivatives of the McMurry products enabled the separation of the minor undesirable geometrical isomer. The methodology proceeds without E,Z isomerization, employs a very mild final debenzylation step compatible with a large array of functional groups, and can be applied to the generation of a variety of 4-hydroxytamoxifen analogues.
- Detsi, Anastasia,Koufaki, Maria,Calogeropoulou, Theodora
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p. 4608 - 4611
(2007/10/03)
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- Synthesis and Sulfatase Inhibitory Activities of (E)- and (Z)-4-Hydroxytamoxifen Sulfamates
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We report the development of (E)- and (Z)-4-hydroxytamoxifen sulfamates as estrone sulfatase inhibitors, potential therapeutic agents for the treatment of breast cancer. Both compounds competitively inhibit estrone sulfatase isolated from rat liver with apparent Ki of 35.9 μM for (E)-4-hydroxytamoxifen sulfamate and an apparent Ki of >500 μM for the (Z) isomer.
- Chu, Guo-Hua,Peters, Amy,Selcer, Kyle W.,Li, Pui-Kai
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p. 141 - 144
(2007/10/03)
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- Synthesis of Tamoxifen and 4-Hydroxytamoxifen using Super-base-metalated Propylbenzene
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Propylbenzene is metalated regioselectively at the α-carbon using the n-BuLi-t-BuOK-TMEDA super-base combination; the resulting carbanion condenses with functionalised benzophenones to provide direct syntheses of tamoxifen and 4-hydroxytamoxifen.
- Olier-Reuchet, Chantal,Aitken, David J.,Bucourt, Robert,Husson, Henri-Philippe
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p. 8221 - 8224
(2007/10/02)
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- Synthesis of Hydroxytamoxifen
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The synthesis of hydroxytamoxifen, antiestrogenic tetrasubstituted olefin was achieved via palladium-catalyzed cross-coupling of vinyl bromide with arylzinc chloride.
- Al-Hassan, Mohammed I.
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p. 1619 - 1624
(2007/10/02)
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- The Use of the Perfluorotolyl Protecting Group in the Synthesis of Pure Z and E Isomers of 4-Hydroxytamoxifen -1-(4-hydroxyphenyl)-2-phenyl-1-butene>
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The perfluorotolyl protecting group has been used in the synthesis of pure Z and E isomers of 4-hydroxytamoxifen (4a), a potent metabolite of the anticancer drug, tamoxifen (1a). 4-(Perfluorotolyloxy)phenyl magnesium bromide underwent addition to the carbonyl group of the easily prepared versatile ketone, 1--2-phenyl-1-butanone (7), without affecting the chloroethoxy group.Acid catalysed dehydration of the resulting carbinol gave a 1:1 mixture of isomeric ethers, (6a) and (6b), that were easily separated by chromatography and respectively converted to the Z (4a) and E (4b) isomers of 4-hydroxytamoxifen.The property of the perfluorotolyl function in enabling the separation of geometrical isomers is attributed to a combination of its lipophilicity and electron withdrawal.
- McCague, Raymond
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p. 771 - 793
(2007/10/02)
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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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