Characterization of the isomeric configuration and impurities of (Z)-endoxifen by 2D NMR, high resolution LC⬜MS, and quantitative HPLC analysis

Elkins, Phyllis D.; Coleman, Donna P.; Burgess, Jason P.; Gardner, Michael S.; Hines, John W.; Scott, Brendan; Kroenke, M; Larson, Jami; Lightner, Melissa; Turner, Gregory A.; White, Jonathan M.; Liu, Paul

doi:10.1016/j.jpba.2013.07.010

Cited by 23 publications

(14 citation statements)

References 17 publications

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“…The E,E -configurations of the 2,6-dimethyl groups of 1 were confirmed by two-dimensional rotating-frame nuclear Overhauser effect spectroscopy (ROESY) 22 23 24 . These experiments showed no cross-peaks between methyl protons (H a ) at C2 and C6 positions (2.15 ppm) and vinylic protons (H b ) at C1 and C7 positions (7.61 ppm), indicating that these methyl and vinylic protons do not exist in close proximity in space (<5 Å).…”

Section: Resultsmentioning

confidence: 91%

Introduction of Methyl Groups at C2 and C6 Positions Enhances the Antiangiogenesis Activity of Curcumin

Koo

Shin

Choi

et al. 2015

Sci Rep

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Curcumin has diverse biological activities, but is known to undergo rapid metabolism via reduction of vinylic double bonds and phase II conjugation. To prevent reductive metabolism of curcumin, we introduced a methyl group at both C2 and C6 positions (compound 1) or at the C2 position (compound 2) of curcumin, creating steric hindrance on double bonds against metabolizing enzymes. As predicted, these compounds were resistant to reduction by alcohol dehydrogenase. Compound 1 was further evaluated for its antiangiogenesis activity in vitro and in vivo. It exhibited significantly greater inhibitory activity than curcumin against endothelial cell migration, invasion, and tube formation. Similarly, the in vivo Matrigel plug assay in C57BL/6 mice showed more pronounced reduction of blood vessels in the plugs containing 1 than those containing curcumin. Moreover, 1 suppressed tumor growth more effectively than curcumin in a U87MG mouse xenograft model by inhibiting angiogenesis. In vivo metabolite analysis by liquid chromatography/mass spectrometry demonstrated that 1 underwent markedly slower reductive metabolism than curcumin. Taken together, our results indicate that 1 has enhanced antiangiogenesis activity and suppression of tumor growth compared with curcumin, reflecting diminished reductive metabolism owing to the introduction of methyl groups at the C2 and C6 positions of curcumin.

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Section: Resultsmentioning

confidence: 91%

Introduction of Methyl Groups at C2 and C6 Positions Enhances the Antiangiogenesis Activity of Curcumin

Koo

Shin

Choi

et al. 2015

Sci Rep

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“…However, unlike the END concentrations, the 4HT concentrations in the capillary blood samples were lower than in venous blood. Given that these are each complex molecules which are capable of reacting in different ways, potentially resulting in different degradation products and rearrangements, we cannot exclude that the peaks interpreted as 4HT and END during LC–MS/MS also had contributions from products that had similar chromatographic retention times to 4HT and END 14 , 15 . Thus, differences in the products of 4HT and END may have also contributed to the differences in the 4HT and END concentrations.…”

Section: Discussionmentioning

confidence: 99%

Preliminary results using a kit to measure tamoxifen and metabolites concentrations in capillary blood samples from women with breast cancer

Rehnmark¹,

Shabo

Randahl³

et al. 2022

Sci Rep

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The aim of the study was to compare 3 blood sampling methods, including capillary blood sampling, for determining Tamoxifen (TAM), Z-endoxifen (END), and 4-hydroxytamoxifen (4HT) concentrations. High performance liquid chromatography-mass spectrometry was used to quantify concentrations of TAM, END, and 4HT in plasma, venous blood, and capillary blood samples of 16 participants on TAM therapy for breast cancer. The rhelise kit was used for capillary sampling. Calibration curves using 13C-labeled analogs of TAM, END, and 4HT as internal standards were used for quantifications. A capillary sampling kit was used successfully for all participants. Mean TAM concentrations did not differ significantly in the 3 types of samples. Mean END and 4HT concentrations did differ significantly between capillary and venous blood samples, possibly related to photodegradation in the internal standards prior to use or degradation products with chromatographic retention times similar to the metabolites. TAM, END, and 4HT concentrations were relatively stable when stored for 14 days at 8 °C and 20 °C. Therapeutic drug monitoring of TAM using an innovative kit and capillary blood sampling is feasible. Preliminary data from this study will aid in developing a multicenter, randomized clinical trial of personalized TAM dose monitoring and adjustments, with the goal of enhancing the quality-of-life and outcomes of patients with breast cancer. Clinical Trial Identification: EudraCT No 2017-000641-44.

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“…Functionally, Z-Tam acts as an ER antagonist, while E-Tam acts as an ER agonist [23, 24]. Similar differences in affinity and intrinsic activity favoring the Z isomer have also been observed with 4OHT and End [25, 26]. Such distinct modulation of ERs by the E and Z isomers of Tam, 4OHT and End [27] suggest that these isomers might also exhibit novel affinity and activity at CB1 and CB2Rs.…”

Section: Introductionmentioning

confidence: 91%

Tamoxifen Isomers and Metabolites Exhibit Distinct Affinity and Activity at Cannabinoid Receptors: Potential Scaffold for Drug Development

et al. 2016

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Tamoxifen (Tam) is a selective estrogen receptor (ER) modulator (SERM) that is an essential drug to treat ER-positive breast cancer. Aside from known actions at ERs, recent studies have suggested that some SERMs like Tam also exhibit novel activity at cannabinoid subtype 1 and 2 receptors (CB1R and CB2Rs). Interestingly, cis- (E-Tam) and trans- (Z-Tam) isomers of Tam exhibit over a 100-fold difference in affinity for ERs. Therefore, the current study assessed individual isomers of Tam and subsequent cytochrome P450 metabolic products, 4-hydroxytamoxifen (4OHT) and 4-hydroxy-N-desmethyl tamoxifen (End) for affinity and activity at CBRs. Results showed that Z-4OHT, but not Z-Tam or Z-End, exhibits higher affinity for both CB1 and CB2Rs relative to the E-isomer. Furthermore, Z- and E-isomers of Tam and 4OHT show slightly higher affinity for CB2Rs, while both End isomers are relatively CB1R-selective. When functional activity was assessed by G-protein activation and regulation of the downstream effector adenylyl cyclase, all isomers examined act as full CB1 and CB2R inverse agonists. Interestingly, Z-Tam appears to be more efficacious than the full inverse agonist AM630 at CB2Rs, while both Z-Tam and Z-End exhibit characteristics of insurmountable antagonism at CB1 and CB2Rs, respectively. Collectively, these results suggest that the SERMs Tam, 4OHT and End elicit ER-independent actions via CBRs in an isomer-specific manner. As such, this novel structural scaffold might be used to develop therapeutically useful drugs for treatment of a variety of diseases mediated via CBRs.

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Characterization of the isomeric configuration and impurities of (Z)-endoxifen by 2D NMR, high resolution LC⬜MS, and quantitative HPLC analysis

Cited by 23 publications

References 17 publications

Introduction of Methyl Groups at C2 and C6 Positions Enhances the Antiangiogenesis Activity of Curcumin

Introduction of Methyl Groups at C2 and C6 Positions Enhances the Antiangiogenesis Activity of Curcumin

Preliminary results using a kit to measure tamoxifen and metabolites concentrations in capillary blood samples from women with breast cancer

Tamoxifen Isomers and Metabolites Exhibit Distinct Affinity and Activity at Cannabinoid Receptors: Potential Scaffold for Drug Development

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