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Advances in Enzyme Research 2022年第4期10卷 83-100页

作者： Silvia Alejandra Meza-Ireta Blanca Colin-Lozano Penélope Merino-Montiel José Luis Vega-Báez Sara Montiel-Smith Facultad de Ciencias Químicas Ciudad Universitaria Benemérita Universidad Autónoma de Puebla Puebla México

Hormone Receptor positive (HR+) breast cancer is the most common malignancy in women. New strategies in the treatments have targeted the estrogen biosynthesis pathways including the inhibition of the aromatase and 17β-HSD1 enzymes. The present work, describes the study of a new family of 9 hybrid compounds derived from estrone attached to a coumarin fragment, linked through different lengths of hydrocarbon chains. The activity of these compounds was evaluated by molecular docking with two relevant enzymes in breast cancer (HR+). It has been proposed nine compounds as 17β-HSD1 inhibitors and six as aromatase inhibitors. We found important interactions with key amino acids at the orthosteric site of each enzyme and their score values compared to the crystallographic ligand. The in silico analysis showed good score values in the proposed compounds, where the steroidal portion presented important interactions with Met374 and Tyr155 in aromatase and in 17β-HSD1 respectively. Highlighting Compounds 2, 5 and 8 with an aromatic ring at the C4 position of the coumarin moiety, which favored arene-H type interactions essential for protein-ligand recognition. In addition, the results related to the 17β-HSD1 enzyme demonstrated how the length of the linker influences the interaction;the best score was found for derivative 8 with a chain of 8 methylenes.

关键词： Estrone Coumarins aromatase inhibitors 17β-HSD1 inhibitors Molecular Docking

Target-based anticancer indole derivatives and insight into structure-activity relationship:A mechanistic review update(2018—2021)

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3006-3027页

作者： Ashima Dhiman Rupam Sharma Rajesh K.Singh Department of Pharmaceutical Chemistry Shivalik College of PharmacyIKG Punjab Technical UniversityJalandhar 140126India

Cancer,which is the uncontrolled growth of cells,is the second leading cause of death after heart disease.Targeting drugs,especially to specific genes and proteins involved in growth and survival of cancer cells,is the prime need of research world-wide.Indole moiety,which is a combination of aromatic-heterocyclic compounds,is a constructive scaffold for the development of novel leads.Owing to its bioavailability,high unique chemical properties and significant pharmacological behaviours,indole is considered as the most inquisitive scaffold for anticancer drug research.This is illustrated by the fact that the U.S.Food and Drug Administration(FDA)has recently approved several indole-based anticancer agents such as panobinostat,alectinib,sunitinib,osimertinib,anlotinib and nintedanib for clinical use.Furthermore,hundreds of studies on the synthesis and activity of the indole ring have been published in the last three years.Taking into account the facts stated above,we have presented the most recent advances in medicinal chemistry of indole derivatives,encompassing hot articles published between 2018and 2021 in anticancer drug research.The recent advances made towards the synthesis of promising indole-based anticancer compounds that may act via various targets such as topoisomerase,tubulin,apoptosis,aromatase,kinases,etc.,have been discussed.This review also summarizes some of the recent efficient green chemical synthesis for indole rings using various catalysts for the period during 2018—2021.The review also covers the synthesis,structure-activity relationship,and mechanism by which these leads have demonstrated improved and promising anticancer activity.Indole molecules under clinical and preclinical stages are classified into groups based on their cancer targets and presented in tabular form,along with their mechanism of action.The goal of this review article is to point the way for medicinal chemists to design and develop effective indole-based anticancer agents.

关键词： Indole Synthesis Anticancer Structure-activity relationship Topoisomerase Apoptosis aromatase inhibitors Tubulin inhibitors

Medical treatments of endometriosis: a review

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Reproductive and Developmental Medicine 2023年第3期7卷 166-179页

作者： Bahi Elbasueny Maya Geets Emily C.Yang Catherine Allaire Paul J.Yong Mohamed A.Bedaiwy Division of Reproductive Endocrinology and Infertility Department of Obstetrics and GynecologyFaculty of MedicineUniversity of British ColumbiaVancouverBCCanada Department of Obstetrics and Gynecology Faculty of MedicineMenoufia University.MenoufiaEgypt.

Endometriosis is a chronic gynecological disorder that affects approximately 10%of women of reproductive age.Most medical treatments used today for endometriosis pain are hormonal therapies,which are not an option for those trying to conceive and are not tolerated by a subset of patients due to side effects.In this article,we offer a comprehensive review of current and investigational medical therapeutic options used to treat endometriosis pain,as well as a symptom-based systematic approach for patients with painful endometriosis.We have also included recommendations for research to enhance the evolution of novel therapeutic options.A thorough literature search was carried out,and the data were synthesized using a synthesis matrix that classifies and categorizes various arguments.

关键词： Endometriosis Pelvic pain Medical treatment Medical therapy Non-steroidal anti-inflammatory drugs Combined oral contraceptives Progesterone GnRH agonist GnRH antagonist aromatase inhibitors Investigational endometriosis treatments

Management of genitourinary syndrome of menopause in breast cancer survivors:An update

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World Journal of Clinical Oncology 2022年第2期13卷 71-100页

作者： Daniel Maria Lubian Lopez Department of Mother and Child Health and Radiology Faculty of MedicineUniversity of CadizCadiz 11100Spain Department of Obstetrics and Gynecology Service University Hospital of Jerez de la FronteraJerez de la Frontera 11407Spain Department of Obstetrics and Gynecology Hospital Viamed Bahia de CadizChiclana de la Frontera 11130Cadiza Spain Department of Obstetrics and Gynecology Hospital Quironsalud Campo de GibraltarLos Barrios 11379CadizSpain

There is increasing attention about managing the adverse effects of adjuvant therapy(Chemotherapy and anti-estrogen treatment)for breast cancer survivors(BCSs).Vulvovaginal atrophy(VVA),caused by decreased levels of circulating estrogen to urogenital receptors,is commonly experienced by this patients.Women receiving antiestrogen therapy,specifically aromatase inhibitors,often suffer from vaginal dryness,itching,irritation,dyspareunia,and dysuria,collectively known as genitourinary syndrome of menopause(GSM),that it can in turn lead to pain,discomfort,impairment of sexual function and negatively impact on multiple domains of quality of life(QoL).The worsening of QoL in these patients due to GSM symptoms can lead to discontinuation of hormone adjuvant therapies and therefore must be addressed properly.The diagnosis of VVA is confirmed through patient-reported symptoms and gynecological examination of external structures,introitus,and vaginal mucosa.Systemic estrogen treatment is contraindicated in BCSs.In these patients,GSM may be prevented,reduced and managed in most cases but this requires early recognition and appropriate treatment,but it is normally undertreated by oncologists because of fear of cancer recurrence,specifically when considering treatment with vaginal estrogen therapy(VET)because of unknown levels of systemic absorption of estradiol.Lifestyle modifications and nonhormonal treatments(vaginal moisturizers,lubricants,and gels)are the first-line treatment for GSM both in healthy women as BCSs,but when these are not effective for symptom relief,other options can be considered,such as VET,ospemifene,local androgens,intravaginal dehydroepiandrosterone(prasterone),or laser therapy(erbium or CO2 Laser).The present data suggest that these therapies are effective for VVA in BCSs;however,safety remains controversial and a there is a major concern with all of these treatments.We review current evidence for various nonpharmacologic and pharmacologic therapeutic modalities for GSM in BCSs and highlight the subst

关键词： Genitourinary syndrome of menopause Breast cancer survivors aromatase inhibitors Vaginal moisturizers and lubricants Vaginal estrogens Laser

Chinese Medicine Yishen Jiangu Granules(益肾健骨颗粒)on aromatase Inhibitor-Associated Musculoskeletal Symptoms

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Chinese Journal of Integrative Medicine 2018年第11期24卷 867-872页

作者： ZHANG Xing PENG Nan YU Ming-wei ZHANG Gan-lin SUN Xu YANG Guo-wang LI Chen YANG Lin WANG Xiao-min Department of Oncology Beijing Hospital of Traditional Chinese Medicine Affiliated to Capital Medical University Graduate School Beijing University of Chinese Medicine

Objective： To assess the effectiveness of Yishen Jiangu Granules（益肾健骨颗粒, YSJGG） on aromatase inhibitor-associated musculoskeletal symptoms（AIMSS）. Methods： A single-arm, open-label study was conducted in 34 postmenopausal women with breast cancer who experienced AIMSS. Patients were treated with YSJGG for 12 weeks（12.4 g orally twice daily）. The primary outcome was a change in the mean worst pain score of Brief Pain Inventory-Short Form（BPI-SF） over 12 weeks, and the second outcomes included changes in pain severity and pain-related interference of BPI-SF and Western Ontario and McMaster Universities Osteoarthritis Index（WOMAC）, Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands（M-SACRAH）, the Functional Assessment of Cancer Therapy-Breast（FACT-B）, bone mineral density（BMD） and blood indices such as calcium（Ca）, phosphate（P）, and alkaline phosphatase（ALP）. Results： Of 37 women recruited, 30 initiated the therapy and 24 were evaluable at 12 weeks. The primary outcome（BPI-SF worst pain scores） achieved a 2.17-point reduction compared with baseline（5.75±1.87 vs 3.58±2.15, P〈0.01）. There were reductions in pain severity（decreased 1.65, P〈0.01） and pain-related interference（decreased 2.55, P〈0.01）. The changes in WOMAC and M-SACRAH scores were similar to BPI-SF（P〈0.05）. In the FACT-B, only physical wel-being and functional wel-being were improved compared with baseline（P〈0.05）. No clinical differences were found in BMD, Ca, P and ALP. Conclusion： YSJGG is an effective and wel-tolerated agent to reduce AIMSS.

关键词： aromatase inhibitors breast cancer musculoskeletal symptoms Chinese medicine Yishen Jiangu Granules

Steroid Sulfatase Inhibitor Reduces Proliferation of Ishikawa Endometrial Cancer Cells in Co-Culture Systems

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Open Journal of Endocrine and Metabolic Diseases 2016年第9期6卷 193-204页

作者： Mitsuo Nishimoto Masafumi Toyoshima Naomi Shiga Hiroki Utsunomiya Fumihiko Suzuki Satoru Nagase Hidekazu Nishigori Takashi Suzuki Hironobu Sasano Kiyoshi Ito Nobuo Yaegashi Department of Obstetrics and Gynecology Tohoku University School of Medicine Sendai Japan Department of Obstetrics and Gynecology Iwate Prefectural Iwai Hospital Iwate Japan Department of Obstetrics and Gynecology Yamagata University School of Medicine Yamagata Japan Department of Pathology Tohoku University School of Medicine Sendai Japan Department of Disaster Obstetrics and Gynecology International Research Institute of Disaster Science Tohoku University Sendai Japan

Objectives: Estrogens significantly contribute toward the growth and development of endometrial cancers. Two principal pathways have been implicated in the final steps of estrogen synthesis: the steroid sulfatase (STS) and aromatase pathways. In this study, we aimed to evaluate the possible effects of tumor-stromal interactions on local estrogen biosynthesis in endometrial cancer. We also assessed the biological effects of inhibitors of steroid sulfatase and aromatase in the co-culture system compared with usual monocultures. Methods/Materials: We isolated stromal cells from endometrial cancer patients to examine local biosynthesis of estrogens and tumor-stromal interactions. Next we examined the effects of steroid sulfatase inhibitor and aromatase inhibitor in monoculture of endometrial cancer cell line (Ishikawa) and in a co-culture system involving an Ishikawa cells and stromal cells. Results: Estrogen receptor and steroid sulfatase mRNA levels in cancer cells were significantly higher in the co-cultures compared with the monocultures of endometrial cancer cells. Estradiol and androstenediol concentrations were also significantly higher in the co-cultured cells. Proliferation of the cancer cells was significantly increased through the steroid sulfatase pathway, which metabolizes androgens, estrone sulfate, and estradiol sulfate as its substrates. However, its proliferation was significantly decreased by the treatment of steroid sulfatase or aromatase inhibitors. The significant growth inhibition by the steroid sulfatase and aromatase inhibitors were also observed in the co-culture system. Conclusions: We evaluated the effects of STS inhibitor and aromatase inhibitors on the proliferation of estrogen-dependent endometrial cancer cells. Considering that intratumoral estrogen metabolism plays an important role, our co-culture systems provide an environment similar to that of the tumor in living patients in terms of metabolism and synthesis of intratumoral estrogens. The results of this study may aid in achieving

关键词： aromatase inhibitors Co-Culture System Endometrial Cancer Estrogen Estrogen Sulfatase Inhibitor