Browsing by Author "Liu, Jinzhong"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Item
    Design and Synthesis of Norendoxifen Analogues with Dual Aromatase Inhibitory and Estrogen Receptor Modulatory Activities
    (American Chemical Society, 2015-03-26) Lv, Wei; Liu, Jinzhong; Skaar, Todd C.; Flockhart, David A.; Cushman, Mark; Medicine, School of Medicine
    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.
  • Thumbnail Image
    Item
    A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β
    (Elsevier, 2016-11-01) Zhao, Li-Ming; Jin, Hai-Shan; Liu, Jinzhong; Skaar, Todd C.; Ipe, Joseph; Lv, Wei; Flockhart, David A.; Cushman, Mark; Medicine, School of Medicine
    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 = 62.2 nM) while also exhibiting good binding activity to both ER-α (EC50 = 72.1 nM) and ER-β (EC50 = 70.8 nM). In addition, a new synthesis was devised for the preparation of norendoxifen and its analogues through a bis-Suzuki coupling strategy.,
  • Thumbnail Image
    Item
    Synthesis of Triphenylethylene Bisphenols as Aromatase Inhibitors that Also Modulate Estrogen Receptors
    (ACS, 2016) Lv, Wei; Liu, Jinzhong; Skaar, Todd C.; O'Neill, Elizaveta; Yu, Ge; Flockhart, David A.; Cushman, Mark; Department of Medicine, IU School of Medicine
    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 β (ER-β), and antagonize the activity of β-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-β binding affinities of several of the resulting analogues, together with the facts that they antagonize β-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.
  • Thumbnail Image
    Item
    Tamoxifen metabolites can target both aromatase and estrogen receptors
    (2015-11) Liu, Jinzhong; Flockhart, David A.; Desta, Zeruesenay; Georgiadis, Millie M.; Hurley, Thomas D.; Li, Lang; Skaar, Todd C.
    Breast cancer remains the most prevalent malignancy diagnosed in women. More than two thirds of all diagnosed breast cancers are estrogen receptor (ER)-positive and are dependent on estrogen signaling. Drugs for the treatment of ER-positive breast cancer can be divided into three classes: selective estrogen receptor modulators (SERMs), selective estrogen receptor down-regulators (SERDs) and aromatase inhibitors (AIs). However, the efficacy and safety of SERMs, SERDs and AIs are compromised by side effects or tumor resistance. One possible way of improving treatment efficacy and safety profiles is to develop agents with dual aromatase inhibitory and ER modulatory activity. Over the past 30 years, tamoxifen, a SERM, has become the most widely used drug for the adjuvant treatment of breast cancer. The metabolism of tamoxifen has a complex profile involving both active and inactive metabolites, among which endoxifen, 4-hydroxytamoxifen (4-HT) and norendoxifen (Nor) have been shown to have ER modulatory activity. Previous studies have also shown that norendoxifen is a potent AI in vitro. These preliminary studies support the utilization of tamoxifen metabolites as lead compounds for the development of dual AI/SERM(D) agents. Hydroxynorendoxifen (Hdn) was identified as a novel tamoxifen metabolite, with an average plasma concentration of 0.82 nM. Nor and Hdn were potent and relatively selective AIs, with Kis of 70 nM and 20 nM, respectively. Nor and Hdn have high binding affinity for ER-α and ER-β, with EC50 values less than 35 nM. Nor and Hdn can inhibit breast cancer cell proliferation with high potency, with IG50s of 25 nM and 9 nM, respectively. Nor and Hdn can suppress progesterone receptor (PGR) mRNA expression level by reducing it by 68% and 86%. Moreover, a series of Nor analogues were shown to have both potent aromatase inhibitory activity and high ERs binding affinity. Results from this dissertation will contribute to three aspects: 1) the identification of Hdn as a tamoxifen metabolite illustrated a more comprehensive metabolism profile of tamoxifen; 2) the data suggest Nor and Hdn possess dual aromatase inhibitory and ER antagonistic activity; 3) a series of Nor analogues were characterized as lead compounds for the development of dual AI/SERM(D) agents.