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  • br Criteria for ER targeted

    2020-05-14


    Criteria for ER-targeted fluorescent probes
    Survey of fluorescent probes
    Proposed approach to high affinity fluorescent steroidal ER probes Our proposed approach to the development of a new generation of fluorescent estrogen receptor imaging agents employs many of the elements present in the doxorubicin-antiestrogen project. The steroidal component would incorporate the 11β-(4-oxyphenyl) estradiol scaffold associated with high ER affinity, anti-estrogenic properties and metabolic stability. Projecting from the 4-oxyphenyl group, one could append variety of tether lengths and terminal functional groups. One could then identify fluorophores possessing a variety of imaging properties as well as physico-chemical properties. These could then be modified with tethers of various lengths and functionalized with terminal groups complementary to those on the steroidal component. Conjugation using a “click” ligation or other coupling reaction in the final step provides a series of fluorescent agents which should be able to image the presence of ER in a variety of settings, ranging from cells to whole animals. Representative fluorophores, steroids and tethers (linkers) are illustrated in Fig. 21. We have prepared initial examples of such reagents and are in the process of undertaking the coupling reactions. We will describe their properties and applications as they become available.
    Conflict of interests
    Acknowledgements Financial support from the U.S. Department of Energy (DE-SC0001781) is gratefully acknowledged. The authors thank Jessa Silver and Prof Ondrechen for contributing the molecular modeling representation in Fig. 18.
    Introduction Estrogens are hormones that induce a myriad of physiological actions. They play an essential role in pubertal changes in girls through the induction of growth and development of the vagina, uterus, fallopian tubes, and mammary glands. During the menstrual cycle, estrogen produces an environment suitable for fertilization and implantation. Estrogen levels increase during pregnancy and stimulate the hormonal processes necessary for fetal maturation and pregnancy maintenance. In addition, estrogens have important actions in the urinary tract, pelvic muscles, the cardiovascular system, bones, breasts, skin, hair, mucous membranes, the Thiorphan and eating behavior (Arnal et al., 2017; dos Santos, da Silva, Ribeiro Jr., and Stefanon, 2014; Hirschberg, 2012; Manolagas, O\'Brien, and Almeida, 2013; Simpson, 2003; Turgeon, McDonnell, Martin, and Wise, 2004). The ovaries are the major source of circulating estrogen in premenopausal women, with estradiol as the main secretory product. During pregnancy, the placenta is the primary site of estrogen synthesis. Circulating estrogens are bound to serum proteins (sex hormone-binding globulin (SHBG) and albumin) and their biological effects are mediated by their binding to two estrogen receptors (ER): ERα and ERβ. The life expectancy of women has increased from 48 years to over 80 years in a century and many women will spend a large part of their lives in a post-menopausal state. Menopause is defined as the permanent end of menstruation and ovulation due to ovarian failure and thus is characterized by the cessation of estrogen production by the ovaries. Nevertheless, adipose, brain, and bone tissues, as well as the vascular endothelium and aortic smooth muscle cells, can produce small amounts of hormones, through aromatization of testosterone into estradiol, acting locally or systemically. The median age at menopause among white women from industrialized countries ranges between 50 and 52 years (Gold, 2011; Turgeon et al., 2004). The decline in hormone levels in menopausal women can lead to a number of bothersome symptoms. The most common include vasomotor hot flushes and/or night sweats, insomnia and genitourinary disturbances. Profuse sweating and flushing can interfere with sleep, mood, memory, social relationships, and work productivity (Utian, 2005). In addition, menopause is also associated with accelerated bone loss along with an elevated risk of developing osteoporosis and fractures, with an increased risk of cardiovascular events and metabolic disorders. Menopause can also induce genitourinary syndromes, including vulvovaginal atrophy and lower urinary tract symptoms (Portman et al., 2014). These symptoms are usually relieved by the administration of menopausal hormone therapy (MHT) (Baber et al., 2016; Shifren et al., 2014; Stuenkel et al., 2015). Here, we provide a brief historical overview of MHT, and summarize how the modulation of ERα currently helps to conceive or characterize new treatments.