Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer...Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1（MAP1）, MAP2, neurofilament 38（NF38） by different mechanisms of action and at different levels： neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects.展开更多
Based on the principles of the bioisosterism, combination of the active substructures of selective estrogen receptor modulators which are currently therapeutic agents available for the prevention and treatment of vari...Based on the principles of the bioisosterism, combination of the active substructures of selective estrogen receptor modulators which are currently therapeutic agents available for the prevention and treatment of various estrogen dependent diseases, and structural optimization, a novel series of 2-aroyl-3-aryl-6,7-dihydro-5H-furo[3,2-g]- chromen derivatives was designed as potent selective estrogen receptor modulators via molecular docking. The target compounds have been synthesized, and characterized by 1R, proton NMR, ESI-MS, elemental analysis and evaluated for their antitumor activity against human osteosarcoma U2OS-EGFP-4FI2G cell line. Some target compounds showed good inhibition effects on U2OS-EGFP-4F12G cell line and the preliminary structure-activity relationships were discussed.展开更多
Approximately 80% of breast cancers(BC) are estrogen receptor(ER)-positive and thus endocrine therapy(ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adre...Approximately 80% of breast cancers(BC) are estrogen receptor(ER)-positive and thus endocrine therapy(ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of(1) ovarian function suppression(OFS), usually obtained using gonadotropinreleasing hormone agonists(Gn RHa);(2) selective estrogen receptor modulators or down-regulators(SERMs or SERDs); and(3) aromatase inhibitors(AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs(i.e., tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs(i.e., fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type Ⅰ are permanent steroidal inhibitors of aromatase, while type Ⅱ are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs(i.e., anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors(palbociclib) and mammalian target of rapamycin(m TOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.展开更多
Selective estrogen receptor modulators （SERMs） are structurally different com- pounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists and antagonists. Raloxifene is...Selective estrogen receptor modulators （SERMs） are structurally different com- pounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists and antagonists. Raloxifene is the only SERM approved worldwide for the prevention and treatment of postmenopausal osteoporosis. Raloxifene, which has estrogen-like actions on bone, lipids and the coagulation system, and estrogen antagonist effects on the breast and uterus, has undergone very extensive prospective, placebo-controlled, randomized trial evaluation.展开更多
Estrogen has widespread biological actions. Besides sexual organs, estrogen plays an important role in cardiovascular system, central nervous sy s tem and bone tissue. However, the mechanisms of estrogen action are ve...Estrogen has widespread biological actions. Besides sexual organs, estrogen plays an important role in cardiovascular system, central nervous sy s tem and bone tissue. However, the mechanisms of estrogen action are very complex and not fully understood. The actions of estrogen are not identical and even co mpletely different in some organs system. In this review, we will focus on the n ew development of molecular mechanisms of estrogen action.展开更多
基金supported by FIS/IMSS project No.FIS/IMSS/PROT/G13/1216CGA received Beca de Excelencia en Investigación by Fundación IMSS,ACS+1 种基金JJSU received financial support from CIS/IMSSCONACy T,RPA received financial support from USC-CONACYT Postdoctoral Scholars Program
文摘Estrogen receptor modulators are compounds of interest because of their estrogenic agonistic/antagonistic effects and tissue specificity. These compounds have many clinical applications, particularly for breast cancer treatment and osteoporosis in postmenopausal women, as well as for the treatment of climacteric symptoms. Similar to estrogens, neuroprotective effects of estrogen receptor modulators have been described in different models. However, the mechanisms of action of these compounds in the central nervous system have not been fully described. We conducted a systematic search to investigate the effects of estrogen receptor modulators in the central nervous system, focusing on the modulation of cytoskeletal proteins. We found that raloxifene, tamoxifen, and tibolone modulate some cytoskeletal proteins such as tau, microtuble-associated protein 1（MAP1）, MAP2, neurofilament 38（NF38） by different mechanisms of action and at different levels： neuronal microfilaments, intermediate filaments, and microtubule-associated proteins. Finally, we emphasize the importance of the study of these compounds in the treatment of neurodegenerative diseases since they present the benefits of estrogens without their side effects.
基金Supported by the National Natural Science Foundation of China(No20474053)
文摘Based on the principles of the bioisosterism, combination of the active substructures of selective estrogen receptor modulators which are currently therapeutic agents available for the prevention and treatment of various estrogen dependent diseases, and structural optimization, a novel series of 2-aroyl-3-aryl-6,7-dihydro-5H-furo[3,2-g]- chromen derivatives was designed as potent selective estrogen receptor modulators via molecular docking. The target compounds have been synthesized, and characterized by 1R, proton NMR, ESI-MS, elemental analysis and evaluated for their antitumor activity against human osteosarcoma U2OS-EGFP-4FI2G cell line. Some target compounds showed good inhibition effects on U2OS-EGFP-4F12G cell line and the preliminary structure-activity relationships were discussed.
文摘Approximately 80% of breast cancers(BC) are estrogen receptor(ER)-positive and thus endocrine therapy(ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of(1) ovarian function suppression(OFS), usually obtained using gonadotropinreleasing hormone agonists(Gn RHa);(2) selective estrogen receptor modulators or down-regulators(SERMs or SERDs); and(3) aromatase inhibitors(AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs(i.e., tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs(i.e., fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type Ⅰ are permanent steroidal inhibitors of aromatase, while type Ⅱ are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs(i.e., anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors(palbociclib) and mammalian target of rapamycin(m TOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.
文摘Selective estrogen receptor modulators （SERMs） are structurally different com- pounds that interact with intracellular estrogen receptors in target organs as estrogen receptor agonists and antagonists. Raloxifene is the only SERM approved worldwide for the prevention and treatment of postmenopausal osteoporosis. Raloxifene, which has estrogen-like actions on bone, lipids and the coagulation system, and estrogen antagonist effects on the breast and uterus, has undergone very extensive prospective, placebo-controlled, randomized trial evaluation.
文摘Estrogen has widespread biological actions. Besides sexual organs, estrogen plays an important role in cardiovascular system, central nervous sy s tem and bone tissue. However, the mechanisms of estrogen action are very complex and not fully understood. The actions of estrogen are not identical and even co mpletely different in some organs system. In this review, we will focus on the n ew development of molecular mechanisms of estrogen action.
