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Despite being the focal point of decades of research, female breast cancer (BC) continues to be one of the most lethal cancers in the world. Given that 80 % of all diagnosed BC cases are estrogen receptor-positive (ER+) with carcinogenesis driven by estrogen-ERα signalling, current standard of care (SOC) hormone therapies are geared towards modulating the function and expression levels of estrogen and its receptors, ERα and ERß. Currently, aromatase inhibitors (AIs), selective ER modulators (SERMs) and selective ER degraders (SERDs) are clinically prescribed for the management and treatment of ER+ BC, with the anti-aromatase activity of AIs abrogating estrogen biosynthesis, while the anti-estrogenic SERMs and SERDs antagonise and degrade the ER, respectively. The use of SOC hormone therapies is, however, significantly hampered by the onset of severe side-effects and the development of resistance. Given that numerous studies have reported on the beneficial effects of plant compounds and/or extracts and the multiple pathways through which they target ER+ breast carcinogenesis, recent research has focused on the use of dietary chemopreventive agents for BC management. When combined with SOC treatments, several of these plant components and/or extracts have demonstrated improved efficacy and/or synergistic impact. Moreover, despite a lack of in vivo investigations, plant products are generally reported to have a lower side-effect profile than SOC therapies and are therefore thought to be a safer therapeutic choice. Thus, the current review summarizes the findings from the last five years regarding the anti-aromatase and anti-estrogenic activity of plant products, as well as their synergistic anti-ER+ BC effects in combination with SOC therapies.

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Being the most frequently diagnosed disease, breast cancer is mainly classified as ER+ cancers due to the detection of estrogen receptor (ER) expression. Irrespetive of the successes achieved in the treatment of ER+ cancers by the use of selective estrogen receptor modulator (SERM) drugs like tamoxifen, resistance to the drug is a major clinical obstacle. Working on alternative treatment approaches, here, on the basis of mode of action of aromatase for the conversion of androstenedione to oestrogen, a series of compounds was developed. Results of all the experiments performed with these compounds led to the identification of three highly potent compounds 5d, 5e and 7d with their IC50 61.0, 83.0 and 54.0 nM for aromatase. Indicating their effectiveness in the treatment of ER+ cancers, appreciable tumor growth inhibitory activities of these compounds were observed against breast cancer cell lines. Further, the physico-chemical experiments including plasma protein binding, HSA binding, kinetic studies, solubility, ADME properties and molecular modelling studies supported the drug like features of the compounds.

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Azoles, the antifungal pharmaceuticals are emerging as a new class of water contaminants with a potential to influence the endocrine physiology of surrounding aquatic fauna. In this study, we made an attempt to assess the relative efficacy of widely used azoles belonging to two subclasses, i.e., (i) triazoles (letrozole, fluconazole, itraconazole) and (ii) imidazoles (ketaconazole, ornidazole, clotrimazole), on the onset of germinal vesicle breakdown (GVBD) (an initial step in the final maturation of oocytes) in fully grown preovulatory oocytes of zebrafish (Danio rerio) using an in vitro model. Oocytes (> 650 µm) isolated manually from gravid ovaries were exposed to (i) 0.01 and/or 0.1, 1.0, 5.0, 10, 15, and 20 ng/ml and (ii) 1.0, 2.0, 3.0, 4.0, and 5.0 µg/ml of drugs. Zebrafish Ringer's solution (vehicle) and 0.01% ethyl alcohol (solvent) were used as negative controls. 17α, 20 ß-Dihydroxy-4-pregnen-3-one (17α-DHP) and diethylstibestrol (DES), potent inducers of GVBD in fish, were used as positive controls. GVBD was scored hourly from 0-6 h. In negative controls, there were no indications of GVBD even at the 6th hour, while in 17α-DHP- and DES-exposed oocytes, GVBD was initiated from the 1st hour, reaching 80% and 76% respectively at the 6th hour. Among azoles, letrozole induced GVBD in 73-85%, fluconazole (30-33%), itraconazole (23-33%), ketaconazole (46-53%), ornidazole (36-40%), and clotrimazole (30-33%) of oocytes. These results suggest that azole pharmaceuticals induce GVBD in fish oocytes that may be attributed to their variable degree of cytochrome P450 enzyme inhibitor activity.

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Thirty four of indoles bearing sulfonamides (11-44) were synthesized and evaluated for their anti-aromatase activities. Interestingly, all indole derivatives inhibited the aromatase with IC50 range of 0.7-15.3 µM. Indoles (27-36) exerted higher aromatase inhibitory activity than that of ketoconazole. The phenoxy analogs 28 and 34 with methoxy group were shown to be the most potent compounds with sub-micromolar IC50 values (i.e., 0.7 and 0.8 µM, respectively) without affecting to the normal cell line. Molecular docking demonstrated that the indoles 28, 30 and 34 could occupy the same binding site on the aromatase pocket and share several binding residues with those of the natural substrate (androstenedione), which suggested the competitive binding could be the mode of inhibition of the compounds. The most potent analog 28 could mimic H-bond interactions of the natural androstenedione with MET374 and ASP309 residues on the aromatase. QSAR model also revealed that the para-phenoxy indole (28) affords the higher value of electronegativity descriptor MATS6e as well as the higher inhibitory activity compared with that of the ortho-phenoxy compound (34). The study highlighted a series of promising indoles to be potentially developed as novel aromatase inhibitors for therapeutics.

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Exemestane (EXE) treats estrogen receptor positive (ER+) breast cancer in postmenopausal women by inhibiting the estrogen-synthesizing cytochrome P450 CYP19A1. Variability in the severity and incidence of side effects as well as overall drug efficacy may be partially explained by genetic factors, including nonsynonymous variation in CYP19A1, also known as aromatase. The present study identified phase I EXE metabolites in human liver microsomes (HLM) and investigated mechanisms that may alter the extent of systemic estrogen deprivation in EXE-treated women with breast cancer, including whether functional polymorphisms in aromatase cause differential inhibition by EXE and whether EXE metabolites possess anti-aromatase activity. The potency of EXE and ten of its derivatives was measured with HEK293-overexpressed wild type aromatase (CYP19A1*1) using a rapid novel UPLC tandem mass spectrometry method. Of the ten compounds assayed, five were poor inhibitors (IC 50 Ëƒ 50 µmol/L) of wild type aromatase while five others, including the major metabolite, 17ß-dihydroexemestane (17ß-DHE), exhibited moderate potency, with IC 50 values ranging between 1.2 and 7.1 µmol/L. The anti-aromatase activity of EXE was also tested with two common allozymes, aromataseThr201Met (CYP19A1*3) and aromataseArg264Cys (CYP19A1*4). Differential inhibition of variant aromatase is unlikely to account for variable clinical outcomes as EXE-mediated inhibition of aromataseThr201Met (IC 50 = 0.86 ± 0.12 µmol/L) and aromataseArg264Cys (IC 50 = 1.7 ± 0.65 µmol/L) did not significantly differ from wild type (IC 50 = 0.92 ± 0.17 µmol/L). Although less potent than the parent drug, these results suggest that active metabolites may contribute to the therapeutic mechanism of EXE.

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A series of 1,4-disubstituted-1,2,3-triazoles (13-35) containing sulfonamide moiety were synthesized and evaluated for their aromatase inhibitory effects. Most triazoles with open-chain sulfonamide showed significant aromatase inhibitory activity (IC50=1.3-9.4µM). Interestingly, the meta analog of triazole-benzene-sulfonamide (34) bearing 6,7-dimethoxy substituents on the isoquinoline ring displayed the most potent aromatase inhibitory activity (IC50=0.2µM) without affecting normal cell. Molecular docking of these triazoles against aromatase revealed that the compounds could snugly occupy the active site of the enzyme through hydrophobic, π-π stacking, and hydrogen bonding interactions. The potent compound 34 was able to form hydrogen bonds with Met374 and Ser478 which were suggested to be the essential residues for the promising inhibition. The study provides compound 34 as a potential lead molecule of anti-aromatase agent for further development.

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