Hinesol attenuates DSS-induced ulcerative colitis through the suppression of Src-mediated NF-κB and chemokine signaling pathway.

As a common inflammatory bowel disease, ulcerative colitis (UC) is featured with inflammation, oxidative damage, and the impairment of intestinal mucosal barrier, which bring threat to patients' quality of live. Hinesol, derived from Atractylodes lancea, is a unique sesquiterpenoid. Our study proposed to survey the effects and mechanism of hinesol in UC. UC mouse model was constructed using dextran sulfate sodium (DSS). Lipopolysaccharide (LPS) was applied for RAW264.7 cells stimulation to construct cell inflammatory model. The changes of disease activity index (DAI), body weight, colon length, and intestinal pathology in mice were analyzed to estimate the severity of colitis. Enzyme-linked immunosorbent assay was applied to check the changes of interleukin (IL)-1ß, IL-18, IL-6, and tumor necrosis factor (TNF)-α. The levels of myeloperoxidase (MPO), superoxide dismutase (SOD), glutathione peroxidase (GSH-px), catalase (CAT), and malondialdehyde (MDA) were estimated by corresponding reagent kit. The changes of phosphorylated (p)-NF-κB P65, and p-IκBα, ZO-1, Occludin, Claudin-1, Src, XCL1, CCL2, and CXCL16 protein were examined using western blot. Flow cytometry and cell counting kit-8 assay were utilized for assessment of cell apoptosis and viability. We found that DSS reduced mice body weight, increased DAI, shorten colon length, and led to severe enteric mucosal injury, while hinesol improved the above symptoms induced by DSS. In DSS mice, hinesol raised the levels of ZO-1, Occludin, Claudin-1, SOD, GSH-px, and CAT and decreased the levels of TNF-α, IL-18, IL-1ß, IL-6, MPO, and MDA. Additionally, in DSS mice and LPS-stimulated RAW264.7 cells, hinesol inhibited the high expression of Src, XCL1, CCL2, CXCL16, p-NF-κB P65, and p-IκBα. The molecular docking showed that there was a good interaction between hinesol and Src. Moreover, in LPS-stimulated RAW 264.7 cells, Src overexpression partially reversed the inhibition of hinesol on cell apoptosis, pro-inflammatory factors, and oxidative stress. In conclusion, hinesol alleviated DSS-induced colitis, which might have a bearing on the inhibition of Src-mediated NF-κB and chemokine signaling pathway.

Reconstruction of Anterior Mandibular Defect Using Submental Island Flap Pedicled With Mental Artery.

Gingival carcinoma is a common malignant tumor occurring in the anterior area of the mandible, which can be derived from the epithelium of gingival mucosa. Surgical extended resection is the main treatment of gingival cancer, which can lead to anterior mandibular defect including mouth floor and mandible and mucosa of lower lip. According to the size of the defect, the common repair method is free musculocutaneous flap with vascular pedicle or pedicle flap. We present a method of repairing mandibular anterior tooth defect with an island flap pedicled with the mental artery.

Decoding kinase-adverse event associations for small molecule kinase inhibitors.

Small molecule kinase inhibitors (SMKIs) are being approved at a fast pace under expedited programs for anticancer treatment. In this study, we construct a multi-domain dataset from a total of 4638 patients in the registrational trials of 16 FDA-approved SMKIs and employ a machine-learning model to examine the relationships between kinase targets and adverse events (AEs). Internal and external (datasets from two independent SMKIs) validations have been conducted to verify the usefulness of the established model. We systematically evaluate the potential associations between 442 kinases with 2145 AEs and made publicly accessible an interactive web application "Identification of Kinase-Specific Signal" ( https://gongj.shinyapps.io/ml4ki ). The developed model (1) provides a platform for experimentalists to identify and verify undiscovered KI-AE pairs, (2) serves as a precision-medicine tool to mitigate individual patient safety risks by forecasting clinical safety signals and (3) can function as a modern drug development tool to screen and compare SMKI target therapies from the safety perspective.

Characterization of chemical and carbon isotopic compositions of gases during thermochemical sulfate reduction and implications for gas origin and content.

For identifying the occurrence and extent of thermochemical sulfate reduction (TSR) reaction of natural gas and better understanding the chemical and carbon isotopic variations in natural gas reservoirs, high-pressure hydro-pyrolysis with a special designed apparatus was performed using natural gas and various amounts of MgSO4·7H2O at up to 360 °C. The yields, chemical and isotopic compositions of the gases produced during TSR and thermal cracking were measured. As the extent of TSR reaction increased, the concentrations of CH4, CO2 and H2S increased in a nonlinear way, while those of C2H6 and C3H8 decreased. According to the variation of gas content, the TSR reaction of alkane gases can be divided into an uncatalyzed and a catalyzed stage, which is different from previous studies that treated the TSR reaction of alkane gases as a non-autocatalytic reduction process. As the concentration of MgSO4·7H2O increased, the rate of TSR reaction with hydrocarbon gases increased. The concentrations of HSO4- and volume of aqueous phase could be responsible for the different TSR reaction rates in the catalyzed stage. The co-variation of ln(C1/C2) and ln(C2/C3) could be related to the TSR reaction of alkane gases. Our study provides clues for understanding the compositional variations in natural conditions.

Diamondoids and thiadiamondoids generated from hydrothermal pyrolysis of crude oil and TSR experiments.

Diamondoid compounds are widely used to reflect thermal maturation of high mature source rocks or oils and oil cracking extents. However, diamondoids and thiadiamondoids were demonstrated to have newly been generated and decomposed in our hydrothermal pyrolysis of crude oil and TSR experiments. Our results show that adamantanes and diamantanes are generated primarily within the maturity range 0.48-2.1% and 1.2-3.0% EasyRo, respectively. Their formation is enhanced and the decomposition of diamantanes obviously lags at elevated temperatures compared with anhydrous experiments. MDI, EAI, DMAI-1, DMDI-2 may serve as reliable maturity proxies at > ca.1.0% EasyRo, and other isomerization indices (TMAI-1, TMAI-2 and DMAI-2) are effective for the highly mature organic matter at EasyRo > 2.0%. The extent of oil cracking (EOC) calculated from the broadly used (3- + 4-) MD method (Dahl et al. in Nature 399:54-56, 1999) is proven to overestimate, especially for highly cracked samples due to the new generation of (3- + 4-) MD. Still, it can be corrected using a new formula at < 3.0% EasyRo. Other diamondoid-related indices (e.g., EAI, DMDI-2, As/Ds, MAs/MDs, DMAs/DMDs, and DMAs/MDs) can also be used to estimate EOC. However, these indices cannot be applied to TSR-altered petroleum. TSR is experimentally confirmed to generate diamantanes and thiaadmantanes at 1.81% EasyRo likely via direct reactions of reduced S species with hydrocarbons and accelerate the decomposition of diamantanes at > 2.62% EasyRo compared with thermal chemical alteration (TCA). More studies are needed to assess specific mechanisms for the formation of thiadiamondoids under natural conditions.

[Effects of large tumor suppressor homolog 2 gene overexpression on the proliferation and apoptosis of oral squamous cell carcinoma].

OBJECTIVE: To investigate the effect of large tumor suppressor homolog 2 (LATS2) gene overexpression on the proliferation and apoptosis of oral squamous cell carcinoma (OSCC). METHODS: Lentivirous particles were transferred into SCC-25 cell to upregulate LATS2 gene expression. Cell proliferation was detected by CCK-8 assay. Apoptosis was detected through flow cytometry. The expression changes of Bax, Bcl-2, and LATS2 were analyzed by Western blot. RESULTS: Gene transfection increased LATS2 expression. Compared with the control group and pEGFP-control group, SCC-25 cell proliferation in the pGFP-LATS2 group was inhibited, whereas the apoptosis ratio increased (P<0.05). Bcl-2 expression decreased, and Bax expression increased. CONCLUSIONS: Overexpression of LATS2 could inhibit SCC-25 cell proliferation and induce apoptosis.

Lactoferricin B reverses cisplatin resistance in head and neck squamous cell carcinoma cells through targeting PD-L1.

Head and neck squamous cell carcinoma (HNSCC) ranks among the top most common cancers with a poor prognosis. The mechanism of chemoresistance is still not well known. This study is to investigate the programmed death-ligand 1 (PD-L1) expression in HNSCC, and test the effect of lactoferricin B (LfcinB) on chemoresistance and its mechanism. We analyzed 510 HNSCC patients in TCGA database and investigated how CD274 expression was related to patient prognosis. PD-L1 was verified from HNSCC samples at local hospital with immunohistochemistry. PD-L1 expression in the acquired cisplatin-resistant HNSCC cells was examined by PCR and WB in order to test PD-L1-induced chemoresistance. LfcinB inoculation in cisplatin-resistant HNSCC cells and in the nude mice was introduced to test the effect of LfcinB on targeting cisplatin resistance and its mechanism. High CD274 mRNA (>125 FPKM) from TCGA database had a significantly reduced 5-year survival rate, and a lower 5-year survival rate in the chemotherapy and radiotherapy-treated patients (P < .05). PD-L1 overexpression was further supported from analysis of 40 HNSCC specimens. PD-L1 and IL-6 in the established cisplatin-resistant HNSCC cells were shown significantly higher (P < .05). IL-6 and PD-L1 expression were partially inhibited by the anti-IL-6/STAT3 antibody. LfcinB displayed a direct cytotoxic effect on cisplatin-resistant HNSCC cells and HNSCC xenografts of cisplatin-resistant cells in the nude mice displayed significant reduction in tumor volume after LfcinB injection (P < .05). Besides, the increase of IL-6 and PD-L1 in cisplatin-resistant HNSCC cells was abolished in vitro by LfcinB (P < .05). PD-L1 expression in HNSCC cells correlates with poor prognosis and chemoresistance, and LfcinB might provide therapeutic potential in HNSCC patients through modulating IL-6 and PD-L1.

A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review.

Importance: Accelerated approval (AA) is a US Food and Drug Administration (FDA) expedited program intended to speed the approval of drugs and biologics that may demonstrate a meaningful advantage over available therapies for diseases that are serious or life-threatening. Observations: This review describes all malignant hematology and oncology AAs from inception of the program on December 11, 1992, to May 31, 2017. During this period, the FDA granted AA to 64 malignant hematology and oncology products for 93 new indications. Of these AAs, 53 were for new molecular entities. Overall, the end point of response rate, including hematologic response rates, accounted for most AAs (81 [87%]), followed by time-to-event end points of progression-free survival or time to progression (8 [9%]) and disease-free survival or recurrence-free survival (4 [4%]). Single-arm trial designs provided the data for 67 (72%) of the initial AA indications. Of the 93 AAs, 51 (55%) have fulfilled their postmarketing requirement and verified benefit in a median of 3.4 years after their initial AA. Thirty-seven (40%) indications have not yet completed confirmatory trial(s) or verified benefit, and 5 indications receiving AA (5%) have been withdrawn from the market. Conclusions and Relevance: The use of the AA program during the past 25 years has increased over time, and only a small portion of indications under the AA program fail to verify clinical benefit. For patients with serious or life-threatening oncologic diseases, AA brings products to the market years before confirmatory trials are typically completed.

[Significance of Smad4, Smad7 and Caveolin-1 expression in oral mucosa carcinogenesis of Wistar rats].

PURPOSE: To investigate the expression of Smad4, Smad7 and Caveolin-1 in the process of carcinogenesis of oral mucosa in Wistar rats, and to understand the changes of TGF-ß/Smad signaling pathway and Caveolin-1 in oral cancer. METHODS: Palatal mucosal carcinogenesis specimens of Wistar rats were obtained from School of Stomatology, Zhengzhou University, which included 5 samples of normal mucosa, 10 samples of simple hyperplasia mucosa, 6 samples of mild mucosal dysplasia, 7 samples of moderate mucosal dysplasia, 13 samples of mucosa severe mucosal dysplasia, and 28 samples of oral cancer tissue. The expression of Smad4, Smad7 and Caveolin-1 was detected by immunohistochemistry. SPSS15.0 software package was used for statistical analysis. RESULTS: The expression of Smad4 decreased in normal and hyperplastic epithelia, dysplasticepithelia and oral cancer gradually, the difference of the expression among the three groups was significant (P<0.05). The expression of Smad7 and Caveolin-1 increased in normal and hyperplastic epithelia, dysplasticepithelia and oral cancer gradually, respectively; the difference of the expression among the 3 groups was significant (P<0.05). Spearman correlation analysis showed that Smad4 was negatively correlated with Smad7, Smad4 was negatively correlated with caveolin-1, Smad7 was positively correlated with Caveolin-1 (P<0.05). CONCLUSIONS: Synergistic effects may exist among Smad4, Smad7 and caveolin-1 in carcinogenesis of oral cancer.

Chemoprevention of oral cancer in leukoplakia patients: A systematic review and meta-analysis.

The systematic review and meta-analysis of published randomised controlled trials (RCTs) was conducted to review the effectiveness of current chemopreventive agents in the treatment of oral leukoplakia lesions (OPLs) and prevention of their progression to oral cancer. Material was identified through a retrospective literature search of the electronic PubMed database, Embase and Cochrane Library between 2008 and 2016.Eight RCTs were included for systematic review. The pooled estimate showed a 14% greater chance of responding for those randomised to interventions compared with placebo (Risk Ratio [RR] 1.14, 95% confidence interval [CI] 0.72 to 1.81). The CI from individual studies overlapped. The results suggested that there were no significant differences in comparing clinical responses between chemopreventive agents with placebo in treatment of OPLs. It is time to investigate new agents for oral cancer chemoprevention.

FDA Approval Summary: Rucaparib for the Treatment of Patients with Deleterious BRCA Mutation-Associated Advanced Ovarian Cancer.

On December 19, 2016, the FDA granted accelerated approval to rucaparib (RUBRACA; Clovis Oncology, Inc.) for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)-associated advanced ovarian cancer who have been treated with two or more chemotherapies. The FDA also approved the FoundationFocus CDx BRCA test (Foundation Medicine, Inc.), the first next-generation sequencing-based companion diagnostic, for identifying patients with advanced ovarian cancer eligible for treatment with rucaparib based on detection of deleterious BRCA1 and/or BRCA2 mutations in tumor tissue. Rucaparib's approval was based primarily on efficacy data from 106 patients with BRCA mutation-associated ovarian cancer who had prior treatment with two or more chemotherapies and safety data from 377 patients with ovarian cancer treated with rucaparib 600 mg orally twice daily on two open-label, single-arm trials. Investigator-assessed objective response rate was 54% [57/106; 95% confidence interval (CI), 44-64], and median duration of response was 9.2 months (95% CI, 6.6-11.7). The approved companion diagnostic verified tumor BRCA mutation status retrospectively in 96% (64/67) of patients. Common adverse reactions (≥20%) to rucaparib were nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. This article summarizes the FDA review and data supporting rucaparib's accelerated approval. Clin Cancer Res; 23(23); 7165-70. ©2017 AACRSee related commentary by Kohn et al., p. 7155.

A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and ß.

The design and synthesis of dual aromatase inhibitors/selective estrogen receptor modulators (AI/SERMs) is an attractive strategy for the discovery of new breast cancer therapeutic agents. Previous efforts led to the preparation of norendoxifen (4) derivatives with dual aromatase inhibitory activity and estrogen receptor binding activity. In the present study, some of the structural features of the potent AI letrozole were incorporated into the lead compound (norendoxifen) to afford a series of new dual AI/SERM agents based on a symmetrical diphenylmethylene substructure that eliminates the problem of E,Z isomerization encountered with norendoxifen-based AI/SERMs. Compound 12d had good aromatase inhibitory activity (IC50=62.2nM) while also exhibiting good binding activity to both ER-α (EC50=72.1nM) and ER-ß (EC50=70.8nM). In addition, a new synthesis was devised for the preparation of norendoxifen and its analogues through a bis-Suzuki coupling strategy.

A splicing mutation in VPS4B causes dentin dysplasia I.

BACKGROUND: Dentin dysplasia I (DDI) is a genetically heterogeneous autosomal-dominant disorder characterised by rootless teeth with abnormal pulpal morphology, the aetiology of which presents as genetically heterogeneous. METHODS AND RESULTS: Using a cohort of a large Chinese family with 10 patients with DDI, we mapped to a 9.63 Mb candidate region for DDI on chromosome 18q21.2-q21.33. We then identified a mutation IVS7+46C>G which resulted in a novel donor splice site in intron 7 of the VPS4B gene with co-segregation of all 10 affected individuals in this family. The aberrant transcripts encompassing a new insert of 45 bp in size were detected in gingival cells from affected individuals. Protein structure prediction showed that a 15-amino acid insertion altered the ATP-binding cassette of VPS4B. The mutation resulted in significantly reduced expression of mRNA and protein and altered subcellular localisation of VPS4B, indicating a loss of function of VPS4B. Using human gingival fibroblasts, the VPS4B gene was found to act as an upstream transducer linked to Wnt/ß-catenin signalling and regulating odontogenesis. Furthermore, knockdown of vps4b in zebrafish recapitulated the reduction of tooth size and absence of teeth similar to the tooth phenotype exhibited in DDI index cases, and the zebrafish mutant phenotype could be partially rescued by wild-type human VPS4B mRNA. We also observed that vps4b depletion in the zebrafish negatively regulates the expression of some major genes involved in odontogenesis. CONCLUSIONS: This study identifies VPS4B as a disease-causing gene for DDI, which is one of the important contributors to tooth formation, through the Wnt/ß-catenin signalling pathway.

Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors That Also Modulate Estrogen Receptors.

A series of triphenylethylene bisphenol analogues of the selective estrogen receptor modulator (SERM) tamoxifen were synthesized and evaluated for their abilities to inhibit aromatase, bind to estrogen receptor α (ER-α) and estrogen receptor ß (ER-ß), and antagonize the activity of ß-estradiol in MCF-7 human breast cancer cells. The long-range goal has been to create dual aromatase inhibitor (AI)/selective estrogen receptor modulators (SERMs). The hypothesis is that in normal tissue the estrogenic SERM activity of a dual AI/SERM could attenuate the undesired effects stemming from global estrogen depletion caused by the AI activity of a dual AI/SERM, while in breast cancer tissue the antiestrogenic SERM activity of a dual AI/SERM could act synergistically with AI activity to enhance the antiproliferative effect. The potent aromatase inhibitory activities and high ER-α and ER-ß binding affinities of several of the resulting analogues, together with the facts that they antagonize ß-estradiol in a functional assay in MCF-7 human breast cancer cells and they have no E/Z isomers, support their further development in order to obtain dual AI/SERM agents for breast cancer treatment.

Design and synthesis of norendoxifen analogues with dual aromatase inhibitory and estrogen receptor modulatory activities.

Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for treatment of breast cancer. Our previous efforts led to the discovery of norendoxifen as the first compound with dual aromatase inhibitory and estrogen receptor binding activities. To optimize its efficacy and aromatase selectivity versus other cytochrome P450 enzymes, a series of structurally related norendoxifen analogues were designed and synthesized. The most potent compound, 4'-hydroxynorendoxifen (10), displayed elevated inhibitory potency against aromatase and enhanced affinity for estrogen receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 enzymes was also superior to norendoxifen. 4'-Hydroxynorendoxifen is therefore an interesting lead for further development to obtain new anticancer agents of potential value for the treatment of breast cancer.

Antitumor effect of TRAIL on oral squamous cell carcinoma using magnetic nanoparticle-mediated gene expression.

We developed a new magnetic nanovector to improve the efficiency and targeting of transgene therapy for oral squamous cell carcinoma (OSCC). Positively charged polymer PEI-modified Fe(3)O(4) magnetic nanoparticles were tested as gene transfer vectors in the presence of a magnetic field. The Fe(3)O(4) nanoparticles were prepared by a co-precipitation method and had good dispersibility in water. These nanoparticles modified by PEI were combined with negatively charged pACTERT-EGFP via electrostatic interaction. The transfection efficiency of the magnetic nano-gene vector with the magnetic field was determined by a fluorescence-inverted microscope and flow cytometry. The results showed significant improvement compared with the control group (p < 0.05). The magnetic complexes also exhibited up to 6-times higher transfection efficiency compared with commonly used PEI or lipofectin. On the basis of these results, the antitumor effect with suicide gene therapy using pACTERT-TRAIL in vitro and vivo was evaluated. In vitro apoptosis was determined with the Annexin V-FITC Apoptosis Detection Kit. The results suggested that PEI-modified Fe(3)O(4) nanoparticles could mediate the killing of Tca83 cells. Furthermore, treatment with pACTERT-TRAIL delivered by magnetic nanoparticles showed a significant cytostatic effect through the induction of apoptosis in a xenograft model. This indicates that magnetic nano-gene vectors could improve the transgene efficiency for Tca83 cells and could exhibit antitumor functions with the plasmid pACTERT-TRAIL. This may be a new way to treat OSCC.

Differentiation of rabbit bone mesenchymal stem cells into endothelial cells in vitro and promotion of defective bone regeneration in vivo.

Tissue engineering strategies often fail to regenerate bones because of inadequate vascularization, especially in the reconstruction of large segmental bone defects. Large volumes of vascular endothelial cells (ECs) that functionally interact with osteoblasts during osteogenesis are difficult to obtain. In this study, we simulated bone healing by co-culturing differentiated ECs and mesenchymal stem cells (MSCs) either on a culture plate or on a polylactide glycolic acid (PLGA) scaffold in vitro. We also evaluated the effect of osteogenesis in repairing rabbit mandible defects in vivo. In this study, MSCs were separated from rabbit as the seed cells. After passage, the MSCs were cultured in an EC-conditioned medium to differentiate into ECs. Immunohistochemical staining analysis with CD34 showed that the induced cells had the characteristics of ECs and MSC. The induced ECs were co-cultured in vitro, and the induction of MSCs to osteoblast served as the control. Alkaline phosphatase (ALP) and alizarin red (AZR) staining experiments were performed, and the Coomassie brilliant blue total protein and ALP activity were measured. The MSCs proliferated and differentiated into osteoblast-like cells through direct contact between the derived ECs and MSCs. The co-cultured cells were seeded on PLGA scaffold to repair 1 cm mandible defects in the rabbit. The effectiveness of the repairs was assessed through soft X-ray and histological analyses. The main findings indicated that MSCs survived well on the scaffold and that the scaffold is biocompatible and noncytotoxic. The results demonstrated that the co-cultured MSC-derived ECs improved MSC osteogenesis and promoted new bone formation. This study may serve as a basis for the use of in vitro co-culturing techniques as an improvisation to bone tissue engineering for the repair of large bone defects.

Inhibition of cytochrome p450 enzymes by the e- and z-isomers of norendoxifen.

Aromatase catalyzes the conversion of testosterone to estradiol and is the main source of endogenous estrogen in postmenopausal women. Aromatase inhibitors (AIs) are used to treat postmenopausal women with hormone receptor-positive breast cancer. Norendoxifen [4-(1-(4-(2-aminoethoxy)phenyl)-2-phenylbut-1-en-1-yl)phenol], an active metabolite of the selective estrogen receptor modulator tamoxifen, has been shown to be a potent competitive AI, with an IC50 of 90 nM. To obtain data relevant to the clinical use of norendoxifen, the primary objective of this study was to investigate norendoxifen's inhibitory capability on enzymes related to drug-drug interactions. We determined the inhibitory ability of norendoxifen against important drug-metabolizing cytochrome P450 enzymes, including CYP1A2, CYP2A6, CYP3A4, CYP3A5, and CYP2C19, to establish the potency of norendoxifen as a potential cause of drug-drug interactions. A second objective was to determine the effects of E- and Z-norendoxifen on the inhibition of these enzymes to further characterize the isomers' selectivity. The inhibitory abilities of E-, mixed, and Z-norendoxifen against recombinant aromatase (CYP19), CYP1A2, CYP3A4, CYP3A5, and CYP2C19 were tested using microsomal incubations. Mixed norendoxifen inhibited these enzymes with Ki values of 70 ± 9, 76 ± 3, 375 ± 6, 829 ± 62, and 0.56 ± 0.02 nM, respectively. E-Norendoxifen had a 9.3-fold-higher inhibitory ability than Z-norendoxifen against CYP19, while E- and Z-norendoxifen had similar potencies against CYP1A2, CYP3A4, CYP3A5, and CYP2C19. These results suggest that norendoxifen is able to act as a potent AI, and that its E-isomer is 9.3-fold more potent than the Z-isomer.

Synthesis of mixed (E,Z)-, (E)-, and (Z)-norendoxifen with dual aromatase inhibitory and estrogen receptor modulatory activities.

The first synthesis of the tamoxifen metabolite norendoxifen is reported. This included syntheses of (E)-norendoxifen, (Z)-norendoxifen, and (E,Z)-norendoxifen isomers. (Z)-Norendoxifen displayed affinity for aromatase (Ki 442 nM), estrogen receptor-α (EC50 17 nM), and estrogen receptor-ß (EC50 27.5 nM), while the corresponding values for (E)-norendoxifen were aromatase (Ki 48 nM), estrogen receptor-α (EC50 58.7 nM), and estrogen receptor-ß (EC50 78.5 nM). Docking and energy minimization studies were performed with (E)-norendoxifen on aromatase, and the results provide a foundation for structure-based drug design. The oral pharmacokinetic parameters for (E,Z)-norendoxifen were determined in mice, and (Z)-norendoxifen was found to result in significantly higher plasma concentrations and exposures (AUC values) than (E)-norendoxifen. The affinities of both isomers for aromatase and the estrogen receptors, as well as the pharmacokinetic results, support the further development of norendoxifen and its analogues for breast cancer treatment.