Inhibition Of Aromatase Activity Research Articles

The antiestrogen endoxifen protects rat liver mitochondria from permeability transition pore opening and oxidative stress at concentrations that do not affect the phosphorylation efficiency

Endoxifen (EDX) is a key active metabolite of tamoxifen (TAM) with higher affinity and specificity to estrogen receptors that also inhibits aromatase activity. It is safe and well tolerated by healthy humans, but its use requires toxicological characterization. In this study, the effects of EDX on mitochondria, the primary targets for xenobiotic-induced toxicity, were monitored to clarify its potential side effects. EDX up to 30nmol/mg protein did not affect the mitochondrial oxidative phosphorylation. At 50nmol EDX/mg protein, EDX decreased the ADP phosphorylation rate and a partial collapse of mitochondrial membrane potential (Δψ), that parallels a state 4 stimulation, was observed. As the stimulation of state 4 was not inhibited by oligomycin and 50nmol EDX/mg protein caused a slight decrease in the light scattering of mitochondria, these data suggest that EDX promotes membrane permeabilization to protons, whereas TAM at the same concentration induced mitochondrial membrane disruption. Moreover, EDX at 10nmol/mg protein prevented and reversed the Ca2+-induced depolarization of ΔΨ and the release of mitochondrial Ca2+, similarly to cyclosporine A, indicating that EDX did not affect Ca2+ uptake, but directly interfered with the proteins of the mitochondrial permeability transition (MPT) megacomplex, inhibiting MPT induction. At this concentration, EDX exhibited antioxidant activity that may account for the protective effect against MPT pore opening. In conclusion, EDX within the range of concentrations reached in tissues did not significantly damage the bioenergetic functions of mitochondria, contrarily to the prodrug TAM, and prevented the MPT pore opening and the oxidative stress in mitochondria, supporting that EDX may be a less toxic drug for women with breast carcinoma.

Aromatase inhibitor treatment limits progression of peritoneal endometriosis in baboons

To determine the effect of inhibiting aromatase activity on endometrial lesion growth and aromatase expression in a baboon model of induced endometriosis. Prospective study. Primate research institute. Sixteen olive baboons. Sixteen olive baboons with induced endometriosis were examined with laparoscopy 10 months after disease inoculation. Animals in group 1 (n = 10) were treated with 1.25 mg/d of the aromatase inhibitor (AI) letrozole, and animals in group 2 (n = 6) were given a placebo for a total of 6 months. Total number of endometriotic lesions, morphology, and volume of lesions, as well as semiquantitative reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction for levels of aromatase cytochrome messenger RNA were measured. Ovarian volumes were evaluated before treatment initiation and every 2 months during the study. Treatment of group 1 animals with an AI significantly decreased lesion volume from baseline measurements, whereas the placebo-treated animals showed an increase in lesion volume. Aromatase messenger RNA levels in lesions in the AI-treated animals were significantly lower compared with the placebo-treated animals. Ovarian volumes were significantly increased at 6 months of AI treatment compared with pretreatment volumes. These findings suggest that suppression of aromatase cytochrome P450 may inhibit the invivo growth of endometriotic lesions in baboons.

Abstract OT2-2-04: A phase III randomized, placebo-controlled clinical trial evaluating the use of adjuvant endocrine therapy +/− one year of everolimus in patients with high-risk, hormone receptor- (HR) positive and HER2-negative breast cancer: SWOG/NSABP S1207.

Abstract BACKGROUND: Abnormalities of the PI3kinase/AKT/mTOR signaling network are some of the most common molecular anomalies in breast cancer. This pathway has been associated with resistance to endocrine therapies among HR-positive breast tumors. Everolimus, an mTOR-inhibitor, has been shown to increase the biological activity of aromatase inhibitors. In the metastatic setting, everolimus in combination with tamoxifen or exemestane increased the progression-free survival in patients previously treated with endocrine therapy. S1207 proposes to evaluate the role of everolimus used in combination with endocrine therapy in the adjuvant setting. SPECIFIC AIMS/TRIAL DESIGN: S1207 is a SWOG/NSABP randomized phase III double-blind, placebo-controlled clinical trial. The primary objective of the study is to assess whether the addition of one year of everolimus to standard adjuvant endocrine therapy improves invasive disease-free survival (DFS) among patients with high risk HR-positive breast cancer. Secondary objectives include overall survival, distant recurrence-free survival, safety, adherence and quality of life. Submission of tissue specimens/blood samples is required for translational studies. Patients will be randomized to receive standard adjuvant endocrine therapy (selected by treating physician) in combination with one year of everolimus (10 mg PO daily) or standard adjuvant endocrine therapy in combination with one year of matched placebo. ELIGIBILITY CRITERIA: Patients with histologically confirmed invasive breast cancer HER2-negative and HR-positive with high risk features including: 1) node-negative disease with tumors ≥2cm and a recurrence score (RS) >25; 2) 1–3 positive nodes and RS >25; 3) patients with ≥4 positive lymph nodes regardless of RS. Patients with ≥4 positive lymph nodes after completing neoadjuvant chemotherapy are also eligible. All patients must have completed surgery, adjuvant/neoadjuvant chemotherapy, and radiation therapy (if indicated) before registration. Prior exposure to mTOR inhibitors is not allowed. STATISTICAL METHODS/TARGET ACCRUAL: This is a parallel randomization design with equal allocation to the two treatment groups (everolimus and placebo). Randomization is stratified by 4 risk groups. All analyses are intent-to-treat by randomized assignment of eligible patients. The study plans to randomize 3,500 patients over a 3.5-year accrual period with the primary analysis conducted 3 years after the last patient is randomized. The study has 90% power (with 2-sided α=0.05) to detect an effective hazard ratio of 0.75 for everolimus versus placebo, corresponding to a gain in DFS of approximately 4.3% at 5 years. All patients will be followed for 10 years to assess overall survival and late adverse events. The expected trial duration from activation to reporting of DFS is about 7 years. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT2-2-04.

Immunoprecipitation coupled with HPLC–MS/MS to discover the aromatase ligands from Glycyrrhiza uralensis

Affinity chromatography, applied to discover the enzyme inhibitors, needs special column with target protein and its carrier. Selection of stationary phase and mobile phase needs careful considerations due to the characteristics of proteins. In this study, a method immunoprecipitation (IP) coupled with HPLC-DAD–MS was developed to discover the aromatase ligands from Glycyrrhiza uralensis. An SB-C18 column was employed to separate target compounds without special consideration in mobile phase. Twenty-one compounds, including isolated compounds 4, 7, 8, 10, 11, 13, 15, 18–20, 23 and non-isolated compounds A-J, were found to have good affinity to aromatase by LC–MS. Seven of them (7, 15, 18, 19, 23, D, E) were detected to bind with aromatase in MCF-7 cells by IP coupled with HPLC–MS/MS. Bioassays disclosed aromatase inhibitory activities of the isolated compounds mentioned above, verifying the efficiency of IP coupled with HPLC–MS/MS as a method to screen aromatase ligands.

Prostaglandin E2 Stimulates Estradiol Synthesis in the Cerebellum Postnatally with Associated Effects on Purkinje Neuron Dendritic Arbor and Electrophysiological Properties

Prostaglandins (PGs) are ubiquitous membrane-derived, lipid-signaling molecules with wide ranging effects throughout the body. In the brain, PGE(2) is the key regulator of fever after inflammation but is also implicated in neural development and synaptic plasticity. The steroid hormone estradiol is also a key regulator of neural development and synaptic plasticity. Recently, we showed that administering cyclooxygenase (COX) inhibitors to block PGE(2) production increased the total length of Purkinje cell dendrites, the number of dendritic spines, and the level of spinophilin protein, which is enriched in dendritic spines. Correspondingly, PGE(2) administration into the cerebellum decreased spinophilin protein content. We now report that PGE(2) stimulates estradiol synthesis in the immature rat cerebellum via enhanced activity of the aromatase enzyme. Treatment with cyclooxygenase inhibitors reduced cerebellar aromatase activity and estradiol content whereas PGE(2) administration increased both. Treatment with either PGE(2) or estradiol stunted Purkinje neuron dendritic length and complexity and produced a corresponding reduction in spinophilin content. Treatment with formestane to inhibit aromatase activity led to excessive sprouting of the dendritic tree, whereas elevated estradiol had the opposite effect. Electrophysiological measurements from Purkinje neurons revealed novel sex differences in input resistance and membrane capacitance that were abolished by estradiol exposure, whereas a sex difference in the amplitude of the afterhyperpolarization after an action potential was not. Correlated changes in action potential threshold suggest that prolonged alterations in neuronal firing activity could be a consequence of increased estradiol content during the second week of life. These findings reveal a previously unappreciated role for PG-stimulated steroidogenesis in the developing brain and a new potential route for inflammation-mediated disruption of neuronal maturation.

Dynamic changes in brain aromatase activity following sexual interactions in males: Where, when and why?

It is increasingly recognized that estrogens produce rapid and transient effects at many neural sites ultimately impacting physiological and behavioral endpoints. The ability of estrogens to acutely regulate cellular processes implies that their concentration should also be rapidly fine-tuned. Accordingly, rapid changes in the catalytic activity of aromatase, the limiting enzyme for estrogen synthesis, have been identified that could serve as a regulatory mechanism of local estrogen concentrations. However, the precise anatomical localization, time-course, triggering stimuli and functional significance of these enzymatic changes in vivo are not well understood. To address these issues as to where, when and why aromatase activity (AA) rapidly changes after sexual interactions, AA was assayed in six populations of aromatase-expressing cells microdissected from the brain of male quail that experienced varying durations of visual exposure to or copulation with a female. Sexual interactions resulted in a rapid AA inhibition. This inhibition occurred in specific brain regions (including the medial preoptic nucleus), in a context-dependent fashion and time-scale suggestive of post-translational modifications of the enzyme. Interestingly, the enzymatic fluctuations occurring in the preoptic area followed rather than preceded copulation and were tied specifically to the female's presence. This pattern of enzymatic changes suggests that rapid estrogen effects are important during the motivational phase of the behavior to trigger physiological events essential to activate mate search and copulation.

Synthesis and aromatase inhibitory activity of some new 16E-arylidenosteroids

A new series of 16E-arylidene androstene derivatives has been synthesized and evaluated for aromatase inhibitory activity. The impact of various aryl substituents at 16 position of the steroid skeleton on aromatase inhibitory activity has been observed. The 16E-arylidenosteroids 6, 10 and 11 exhibited significant inhibition of the aromatase enzyme. 16-(4-Pyridylmethylene)-4-androstene-3,17-dione (6, IC50: 5.2μM) and 16-(benzo-[1,3]dioxol-5-ylmethylene)androsta-1,4-diene-3,17-dione (11, IC50: 6.4μM) were found to be approximately five times more potent in comparison to aminoglutethimide.

Inhibitory Effect of Luteolin on Estrogen Biosynthesis in Human Ovarian Granulosa Cells by Suppression of Aromatase (CYP19)

Inhibition of aromatase, the key enzyme in estrogen biosynthesis, is an important strategy in the treatment of breast cancer. Several dietary flavonoids show aromatase inhibitory activity, but their tissue specificity and mechanism remain unclear. This study found that the dietary flavonoid luteolin potently inhibited estrogen biosynthesis in a dose- and time-dependent manner in KGN cells derived from human ovarian granulosa cells, the major source of estrogens in premenopausal women. Luteolin decreased aromatase mRNA and protein expression in KGN cells. Luteolin also promoted aromatase protein degradation and inhibited estrogen biosynthesis in aromatase-expressing HEK293A cells, but had no effect on recombinant expressed aromatase. Estrogen biosynthesis in KGN cells was inhibited with differing potencies by extracts of onion and bird chili and by four other dietary flavonoids: kaempferol, quercetin, myricetin, and isorhamnetin. The present study suggests that luteolin inhibits estrogen biosynthesis by decreasing aromatase expression and destabilizing aromatase protein, and it warrants further investigation as a potential treatment for estrogen-dependent cancers.

Thiazolidinediones (TZDs) Affect Osteoblast Viability and Biomarkers Independently of the TZD Effects on Aromatase

Thiazolidinediones (TZDs) are insulin sensitizers used for treatment of diabetes. We have previously reported that TZDs reduce estrogen synthesis by inhibiting aromatase activity in human granulosa cells (HGC). Multiple clinical trials demonstrated that TZDs increase the risk of fractures in postmenopausal women with type 2 diabetes. We studied mouse osteoblasts alone or in a co-culture with HGC to determine whether TZD inhibition of aromatase plays a role in their effects on bone metabolism. Mouse osteoblasts were cultured with and without HGC, and incubated in a medium with or without testosterone, pioglitazone or rosiglitazone. Cell growth, oleic acid uptake, alkaline phosphatase activity, and osteocalcin production were measured. TZDs inhibited estradiol production by up to 84% in HGC/mouse osteoblast co-cultures. TZDs induced mouse osteoblast death and increased oleic acid uptake. TZDs also inhibited alkaline phosphatase activity (58-75%, p<0.046) and osteocalcin production (52-75%, p<0.031). For all the parameters, there were no significant differences between the osteoblast cultures alone and the HCG/osteoblast co-cultures. TZD effects on osteoblast viability, oleic acid uptake, alkaline phosphatase and osteocalcin production are independent of their effects on aromatase.

Neoflavonoids and Tetrahydroquinolones as Possible Cancer Chemopreventive Agents

Several lactone- and lactam-based neoflavonoids and tetrahydroquinolones were synthesized and evaluated for cancer chemopreventive studies using cell and molecular target-based in vitro bioassays, namely NFκB, aromatase, and quinone reductase 1. These analogs blocked TNF-α-induced NFκB activation in a dose-dependent manner with IC₅₀ values in the range of 0.11-3.2 μM. In addition, compound 8 inhibited aromatase activity with an IC₅₀ value of 12.12 μM, and compound 10 affected quinone reductase 1 induction (IR, 3.6; CD, 19.57 μM). Neoflavonoids 8 and 10 exhibiting good results can further be optimized for improved therapeutic profiles. However, investigations into the actions of neoflavonoids and tetrahydroquinolones, especially those related to the NFκB signaling pathway, aromatase inhibition, induction of quinone reductase 1 expression, and in vivo studies could provide new insights into the cancer chemopreventive ability of these molecules.

Zoledronic acid inhibits aromatase activity and phosphorylation: Potential mechanism for additive zoledronic acid and letrozole drug interaction

Zoledronic acid (ZA), a bisphosphonate originally indicated for use in osteoporosis, has been reported to exert a direct effect on breast cancer cells, although the mechanism of this effect is currently unknown. Data from the ABCSG-12 and ZO-FAST clinical trials suggest that treatment with the combination of ZA and aromatase inhibitors (AI) result in increased disease free survival in breast cancer patients over AI alone. To determine whether the mechanism of this combination involved inhibition of aromatase, AC-1 cells (MCF-7 human breast cancer cells transfected with an aromatase construct) were treated simultaneously with combinations of ZA and AI letrozole. This combination significantly increased inhibition of aromatase activity of AC-1 cells when compared to letrozole alone. Treatment of 1nM letrozole in combination with 1μM or 10μM ZA resulted in an additive drug interaction on inhibition of cell viability, as measured by MTT assay. Treatment with ZA was found to inhibit phosphorylation of aromatase on serine residues. Zoledronic acid was also shown to be more effective in inhibiting cell viability in aromatase transfected AC-1 cells when compared to inhibition of cell viability observed in non-transfected MCF-7. Estradiol was able to partially rescue the effect of 1μM and 10μM ZA on cell viability following treatment for 72h, as shown by a shift to the right in the estradiol dose–response curve. In conclusion, these results indicate that the combination of ZA and letrozole results in an additive inhibition of cell viability. Furthermore, ZA alone can inhibit aromatase activity through inhibition of serine phosphorylation events important for aromatase enzymatic activity and contributes to inhibition of cell viability.

Synthesis of imidazole-derived steroidal hybrids as potent aromatase inhibitors

Imidazolyl substituted 16E-arylidenosteroidal derivatives have been synthesized and evaluated for aromatase inhibitory activity. The steroidal hybrids displayed moderate inhibition of the aromatase enzyme. The enzyme activity was monitored by measuring the tritiated H2O released from [1β-3H] androstenedione during aromatization. 16-[3-{3-(Imidazol-1-yl)propoxy}benzylidene]-4-androstene-3,17-dione (10, IC50: 4.4 μM) was found to be seven times more potent in comparison to standard drug aminoglutethimide. New imidazolyl substituted 16E-arylidenosteroidal derivatives have been synthesized and evaluated for aromatase inhibitory activity.

Steroidal carbonitriles as potential aromatase inhibitors

Estrogens, responsible for the growth of hormone-dependant breast cancer are biosynthesized from androgens involving aromatase enzyme in the last rate limiting step. Inhibition of aromatase is an efficient approach for the prevention and treatment of breast cancer. Novel 4-phenylthia derivatives (2, 3 and 7) have been synthesized as aromatase inhibitors. The synthesized compounds (2, 3 and 7) exhibited noticeable enzyme inhibiting activity. Kinetics study of these compounds (2, 3, and 7) showed negligible inhibition of the enzyme under conditions conducive for irreversible inhibition of the enzyme. Introduction of unsaturation at C-4, C-1 & 4 or C-4 & 6 (compounds 5, 9 and 11) was observed to not be an effective strategy for entrancing aromatase inhibiting activity in 17-oxo-16β-carbonitrile derivatives. The d-seco derivatives (13–15 and 17) having unsaturation at C-4, C-1 & 4 or C-4 & 6 along with carbonitrile function in ring-D showed complete loss of aromatase inhibiting activity.

Molecular Modeling Evaluation of Non‐Steroidal Aromatase Inhibitors†

A recent discovery of aromatase crystal structure triggered the efforts to design novel aromatase inhibitors for breast cancer therapy. While correlating docking scores with inhibitory potencies of known ligands, feeble robustness of scoring functions toward prediction was observed. This prompted us to develop new prediction models using stepwise regression analysis based on consensus of different docking and their scoring methods (GOLD, LIGANDFIT, and GLIDE). Quantitative structure-activity relationships were developed between the aromatase inhibitory activity (pIC(50) ) of flavonoid derivatives (n=39) and docking scores and docking descriptors. QSAR models have been validated internally [using leave-one-out cross-validated r(2)(cv) (LOO-Q2))] and externally to ensure the predictive capacity of the models. Model 2 [M2] developed using consensus of docking scores of scoring functions viz. ASP, potential of mean force and DOCK Score (r(2)(cv)=0.850, r(2) = 0.870, r(2)(pred) = 0.633, RMSE = 0.363 μm, r(2)(m(test)) =0.831, r(2)(m(overall)) =0.832) was found to be better in predicting aromatase inhibitory potency (pIC(50) ) compared to the Model 1 [M1] based on docking descriptors (r(2)(cv)= 0.848, r(2) = 0.825, r(2)(pred) =0.788, RMSE=0.421μm, r(2)(m(test)) =0.808, r(2)(m(overall)) =0.821). It has been observed that the natural flavonoids and their derivatives were less potent compared to these scaffolds with imidazolylmethyl substitution owing to the interaction of nitrogen atom of the imidazole ring toward the heme (Fe(3+) ) of the aromatase. Results confirm the potential of our methodology for the design of new potent non-steroidal aromatase inhibitors.

Inhibiton of NFκB activation and aromatase activity by vanilloids: An in vitro and in silico study

AbstractTarget-specific drugs, including natural products, offer promise for the amelioration of cancer and other human ailments with reduced side-effects. Capsaicin, the pungent ingredient present in chillies (Capsicum annuum L.), and capsazepine, a synthetic analogue of capsaicin (collectively referred to as vanilloids), are known to possess a variety of pharmacological and physiological properties. In our continuous effort to discover cancer chemopreventive agents from natural products, we investigated the effect of vanilloids on NFκB activation with stably transfected 293/NFκB-Luc human embryonic kidney cells induced by treatment with tumor necrosis factor (TNFα), and aromatase activity. Capsaicin and capsazepine blocked TNFα-induced NFκB activation in a dose-dependent manner with IC50 values of 13.5 and 8.5 μM, respectively. No cytotoxicity was observed at higher test concentration (20 μg/mL). In addition, these vanilloids inhibited aromatase activity with IC50 values of 0.68 and 4.21 μM, respectively. Computer aided molecular docking studies showed acceptable docking scores indicating good binding affinity of vanilloids with aromatase and NFκB. Based on these findings, aromatase and NFκB are suggested as valid targets for these compounds; additional investigation of chemopreventive or chemotherapeutic potential is required.

Inhibiton of NFκB activation and aromatase activity by vanilloids: An in vitro and in silico study

Target-specific drugs, including natural products, offer promise for the amelioration of cancer and other human ailments with reduced side-effects. Capsaicin, the pungent ingredient present in chillies (Capsicum annuum L.), and capsazepine, a synthetic analogue of capsaicin (collectively referred to as vanilloids), are known to possess a variety of pharmacological and physiological properties. In our continuous effort to discover cancer chemopreventive agents from natural products, we investigated the effect of vanilloids on NFκB activation with stably transfected 293/NFκB-Luc human embryonic kidney cells induced by treatment with tumor necrosis factor (TNFα), and aromatase activity. Capsaicin and capsazepine blocked TNFα-induced NFκB activation in a dose-dependent manner with IC50 values of 13.5 and 8.5 μM, respectively. No cytotoxicity was observed at higher test concentration (20 μg/mL). In addition, these vanilloids inhibited aromatase activity with IC50 values of 0.68 and 4.21 μM, respectively. Computer aided molecular docking studies showed acceptable docking scores indicating good binding affinity of vanilloids with aromatase and NFκB. Based on these findings, aromatase and NFκB are suggested as valid targets for these compounds; additional investigation of chemopreventive or chemotherapeutic potential is required.

Steroidal Metabolites Transformed by Marchantia polymorpha Cultures Block Breast Cancer Estrogen Biosynthesis

Suspension of cultured cells of Marchantia polymorpha have the potential to hydrogenate the olefinic bonds present in androst-1,4-dien-3,17-dione (boldione, 1) to afford dihydroandrost-3,17-dione derivatives including: androst-4-ene-3,17-dione (androstenedione, 4-AD, 2), 5α-androstane-3,17-dione (androstenedione, AD, 4), and the less abundant metabolite 5α-androst-1-ene-3,17-dione (1-androstenedione, 1-AD, 3). After isolation and purification, these metabolites were characterized on the basis of spectroscopic analyses using 1D and 2D NMR as well as mass spectrometry. Cytotoxicity of the biotransformation products against breast adenocarcinoma cells (MCF-7) was assessed by a 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay and cell death (apoptosis or necrosis) was assayed by acridine orange/ethidium bromide staining. Aromatase (cytochrome P450 19 enzyme, CYP19) inhibitory activity was measured by a tritiated water release assay and by direct measurement of bio-transformed steroids using the tritium labeled substrate (3)H-androst-4-ene-3,17-dione. CYP19 mRNA expression in MCF-7 cells was analyzed by real-time PCR. Steroidal products 3 and 4 revealed a highly significant inhibition of MCF-7 cell growth that was predominantly due to apoptosis not necrosis. Steroidal products 3 and 4 are both potent inhibitors of aromatase activity and CYP19 mRNA expression, while 2 is a known substrate for aromatase. These data establish that metabolites 3 and 4 are potent chemical agents against breast cancer via aromatase inhibitory mechanism. Results were interpreted via virtual docking of the biotransformation products to the human placental aromatase active site.

Steroidal pyrazolines evaluated as aromatase and quinone reductase-2 inhibitors for chemoprevention of cancer

The aromatase and quinone reductase-2 inhibition of synthesized heterocyclic pyrazole derivatives fused with steroidal structure for chemoprevention of cancer is reported herein. All compounds were interestingly less toxic than the reference drug (Cyproterone®). The aromatase inhibitory activities of these compounds were much more potent than the lead compound resveratrol, which has an IC50 of 80μM. In addition, all the compounds displayed potent quinone reductase-2 inhibition. Initially the acute toxicity of the compounds was assayed via the determination of their LD50. The aromatase and quinone reductase-2 inhibitors resulting from this study have potential value in the treatment and prevention of cancer.

Optimization of the aromatase inhibitory activities of pyridylthiazole analogues of resveratrol

Aromatase is an established target not only for breast cancer chemotherapy, but also for breast cancer chemoprevention. The moderate and non-selective aromatase inhibitory activity of resveratrol (1) was improved about 100-fold by replacement of the ethylenic bridge with a thiadiazole and the phenyl rings with pyridines (e.g., compound 3). The aromatase inhibitory activity was enhanced over 6000-fold by using a 1,3-thiazole as the central ring and modifying the substituents on the ‘A’ ring to target the Met374 residue of aromatase. On the other hand, targeting the hydroxyl group of Thr310 by a hydrogen-bond acceptor on the ‘B’ ring did not improve the aromatase inhibitory activity.

Depsidones, Aromatase Inhibitors and Radical Scavenging Agents from the Marine-Derived FungusAspergillus unguisCRI282-03

Three new depsidones ( 1, 3, and 4), a new diaryl ether ( 5), and a new natural pyrone ( 9) (synthetically known), together with three known depsidones, nidulin ( 6), nornidulin ( 7), and 2-chlorounguinol ( 8), were isolated from the marine-derived fungus ASPERGILLUS UNGUIS CRI282-03. Aspergillusidone C ( 4) showed the most potent aromatase inhibitory activity with the IC (50) value of 0.74 µM, while depsidones 1, 3, 6- 8 inhibited aromatase with IC (50) values of 1.2-11.2 µM. It was found that the structural feature of depsidones, not their corresponding diaryl ether derivatives (e.g. 5), was important for aromatase inhibitory activity. Aspergillusidones A ( 1) and B ( 3) showed radical scavenging activity in the XXO assay with IC (50) values of 16.0 and < 15.6 µM, respectively. Compounds 1 and 3- 7 were mostly inactive or showed only weak cytotoxic activity against HuCCA-1, HepG2, A549, and MOLT-3 cancer cell lines.