Potent Aromatase Inhibitor Research Articles

Further transformation of fungal catalyzed transformed metabolite 11β-hydroxy-dianabol into new aromatase inhibitors

Secondary biotransformation of 11β-hydroxy-dianabol (11β,17β-dihydroxy-17α-methylandrost-1,4-dien-3-one) (1), catalyzed by using two fungi Gibberella fujikuroi and Cunninghamella blakesleeana at ambient conditions, was carried out to synthesize its analogues. Transformation of compound 1 with G. fujikuroi yielded a new metabolite, 11β, 17β-dihydroxy-17α-methyl-5β-androst-1-ene-3-one (2), while four new derivatives, 6β, 17β-dihydroxy-17α-methylandrost-1,4-diene-3,11-dione (3), 15α,17β-dihydroxy-17α-methylandrost-1,4-diene-3,11-dione (4), 6β,11β,17β-trihydroxy-17α-methylandrost-1,4-dien-3-one (5), and 7β,11β,17β-trihydroxy-17α-methylandrost-1,4-dien-3-one (6) were obtained by transformation with C. blakesleeana. Compounds 1–6 showed a significant aromatase inhibition with IC50 values in the range of 2.01–3.13 μM as compared to the standard drug, exemestane (IC50 = 0.21 ± 0.16 μM). Aromatase is a valid target for drug discovery against ER+ breast cancers. Compounds 1–6 were subjected to molecular docking studies to predict the key interactions, and the MMGBSA studies to analyze the binding affinity and thermal stability of the protein–ligand complexes. Further, the relationship between the metabolites 1–6 and breast tumor androgen receptors was evaluated by in silico approach to analyze the binding interactions between androgen receptors and metabolites. Moreover, compounds 1–6 were found as non-cytotoxic to BJ (Human fibroblast) normal cell line. Hence, these molecules can be further studied for optimization as potential aromatase inhibitors against breast cancer.

Molecular Docking, Synthesis and Biological Evaluation of New Benzimidazole‐Pyridine Derivatives as Potential Aromatase Inhibitor for the Treatment of Cancer

AbstractThis study describes the synthesis of N5‐(4‐(1H‐benzo[d]imidazol‐2‐yl)phenyl)‐N2‐phenylpyridine‐2,5‐diamine derivatives from Orthophenylenediamine (1) and 4‐aminobenzoic acid (2) and all the synthesized chemical moieties screened against a panel of cancer cell lines resulted in the identification compound 6 a with good anti‐cancer potential and a GI50 of 2.95 μM, 3.35 μM, 2.27 μM, 8.46 nM and 1.56 μM against MDAMB‐231, MCF‐7, A‐549, NCI‐H23 and A‐498 respectively. As the second greatest cause of death globally, cancer continues to pose a serious threat to public health. An essential enzyme called aromatase catalyses the last, rate‐limiting step in the production of oestrogens. As a well‐researched endocrine therapeutic strategy, aromatase inhibitors (AIs) efficiently block the production of oestrogen, which is necessary for aromatase activity.

Potential Aromatase Inhibitors from Centella asiatica with Non-synonymous SNPs - A Computational Approach.

Aromatase Inhibitors are used in the treatment of breast cancer as they are effective in decreasing the concentration of estrogen. As SNPs impact the efficacy or toxicity of drugs, evaluating them with mutated conformations would help in identifying potential inhibitors. In recent years, phytocompounds have been under scrutiny for their activity as potential inhibitors. In this study, we have evaluated Centella asiatica compounds for their activity on aromatase with clinically significant SNPs: rs700519, rs78310315 and rs56658716. Using AMDock v.1.5.2, which uses the AutoDock Vina engine, molecular docking simulations were carried out, and the docked complexes were analyzed for their chemical interactions such as Polar contacts using PyMol v2.5. The mutated conformations of the protein and force field energy differences were computationally derived using SwissPDB Viewer. PubChem, dbSNP and ClinVar databases were used to retrieve the compounds and SNPs. ADMET prediction profile was generated using admetSAR v1.0. Docking simulations of the C. asiatica compounds with the native and mutated conformations showed that out of the obtained fourteen phytocompounds, Isoquercetin, Quercetin and9H-Fluorene-2-carboxylic acid were able to dock with best scores in terms of binding affinity (-8.4kcal/mol), Estimated Ki (0.6 µM) values and Polar Contacts in both native and mutated conformations (3EQM, 5JKW, 3S7S). Our computational analyses predict that the deleterious SNPs did not impact the molecular interactions of Isoquercetin, Quercetin and 9H-Fluorene-2-carboxylic acid, providing better lead compounds for further evaluation as potential aromatase inhibitors.

Novel naphthoquinones as potent aromatase inhibitors: Synthesis, anticancer, and in silico studies

A set of 26 naphthoquinone derivatives (3-28) were synthesized by nucleophilic substitution or Michael addition of various amines with 1,4-naphthoquinones and were investigated for their aromatase inhibitory and anticancer activities. The 1,4-naphthoquinone derivatives with amino substituents (14-16 and 24) and the N-alkylated products (25-28) showed promising aromatase inhibitory activity (IC50 = 0.006–2.6 µM). Interestingly, 2-((4-aminophenyl)amino)-3-chloronaphthalene-1,4-dione 14 was noted as a highly potent aromatase inhibitor (IC50 = 6 nM) possessing preferable selective anticancer effect against the breast cancer T47D cell line (IC50: cytotoxic T47D = 24.3 µM, non-cytotoxic to MRC-5 normal cell line, selective index > 6.9). Findings from molecular docking study also suggested that the hydrogen bond formation with Asp309 as well as the pi-sulfur interaction with Met374 residues may be essential for a striking inhibitory effect of the most potent compound 14. Moreover, the in silico drug-likeness prediction indicated that all active naphthoquinone-based compounds are drug-like molecules with potential to be further developed as dual-action anticancer agents for breast cancer management.

Exploring okra-derived compounds as prospective aromatase inhibitors: a computational study for enhanced breast cancer therapy

Estrogen receptor-positive breast cancer represents itself as the most prevalent malignancy among postmenopausal women. One of the promising therapeutic approaches involves the use of Aromatase inhibitors, which competitively bind to Aromatase, reducing estrone and estradiol levels. While current drugs have improved survival rates, they are not without adverse effects. Consequently, this study explores the computational screening of medicinally relevant compounds derived from okra (Abelmoschus esculentus) for potential Aromatase inhibition. Molecular docking employing AMDock v1.5.2 was utilized to assess binding affinities with Aromatase (PDB:3EQM). Subsequently, in-depth molecular interactions were examined using Discovery Studio Visualizer v4.5, and the stability of docked complexes was evaluated via molecular dynamics with the GROMACS package, focusing on RMSD, RMSF, H-bond count, SASA, Free energy landscape, Principal Component Analysis and binding affinity assessment. The pharmacokinetic properties of the okra compounds were predicted using admetSAR v2.0. Our findings highlight Quercetin 3-gentiobioside as a standout candidate, demonstrating superior binding affinity (-10 kcal/mol) and an estimated Ki of 46.77 nM compared to letrozole and other okra compounds. Molecular dynamic analysis confirms the stability of Quercetin 3-gentiobioside binding in terms of H-bonds and conformational integrity. In conclusion, our computational investigation identifies Quercetin 3-gentiobioside, along with Quercetin 3-O-rutinoside and Hyperin, as promising candidates for preclinical studies in the pursuit of potential Aromatase inhibitors. Communicated by Ramaswamy H. Sarma

Evaluation of novel synthesized thiazole derivatives as potential aromatase inhibitors against breast cancer.

Background: 4-Methylacetophenone isused in the preparation of starting materials, 4-methylphenacyle bromide (2) and 4-methylacetophenone thiosemicarbazole (3). Results: Several novel 2,4-disubstituted-1,3-thiazole analogues were obtained via the treatment of starting materials with 4-methylphenacyl bromide, acetyl chloride, aromatic aldehydes and bromination providing thiazole derivatives 5-8 respectively. Conclusion: Compounds 5-8 wereinvestigated for their cytotoxic activity on MCF-7 and normal breast cells. Active compounds were found andin contrast to staurosporine, compound 8 displayed the most potent cytotoxic action that showed a strong inhibitory effect (aromatase) and (protein tyrosine kinase) enzymes, proving that the novel thiazole derivatives promoted the effective anticancer drug candidates.

Evaluating flavonoids as potential aromatase inhibitors for breast cancer treatment: In vitro studies and in silico predictions

Aromatase inhibitors are commonly employed in the treatment of hormone-dependent breast cancers, and flavonoids have emerged as a promising alternative to existing drug classes with unfavorable side effects. In this study, we conducted in vitro investigations into CYP19A1 (aromatase) inhibitory potential of 14 flavonoids, including pinocembrin, sakuranetin, eriodictyol, liquiritigenin, naringenin, hesperetin, flavanone, baicalein, chrysin, nobiletin, luteolin, sinensetin, tricin, and primuletin. Flavonoids displaying inhibitory activity were further assessed using in silico tools, such as molecular docking to predict binding affinities, as well as SwissADME, admetSAR, and QED (Quantitative Estimate of Drug-likeness) for drug-likeness prediction. Flavonoids with IC50 values less than 10 μM, pinocembrin, eriodictyol, naringenin, liquirtigenin, sakuranetin, and chrysin, exhibited favorable physicochemical properties and ADME profiles, suggesting their potential for development as novel flavonoid-based aromatase inhibitors. This study would provide valuable insights for the development of flavonoid-based aromatase inhibitors for the treatment of breast cancer.

Aromatase inhibitors identified from Saraca asoca to treat infertility in women with polycystic ovary syndrome via in silico and in vivo studies

Polycystic ovary syndrome (PCOS) is a widely occurring metabolic disorder causing infertility in 70%–80% of the affected women. Saraca asoca, an ancient medicinal herb, has been shown to have therapeutic effects against infertility and hormonal imbalance in women. This study was aimed to identify new aromatase inhibitors from S. asoca as an alternative to the commercially available ones via in silico and in vivo approaches. For this, 10 previously reported flavonoids from S. asoca were chosen and the pharmacodynamic and pharmacokinetic properties were predicted using tools like Autodock Vina, GROMACS, Gaussian and ADMETLab. Of the 10, procyanidin B2 and luteolin showed better interaction with higher binding energy when docked against aromatase (3S79) as compared to the commercial inhibitor letrozole. These two compounds showed higher stability in molecular dynamic simulations performed for 100 ns. Molecular mechanics Poisson–Boltzmann surface analysis indicated that these compounds have binding free energy similar to the commercial inhibitor, highlighting their great affinity for aromatase. Density functional theory analysis revealed that both compounds have a good energy gap, and ADMET prediction exhibited the drug-likeness of the two compounds. A dose-dependent administration of these two compounds on zebrafish revealed that both the compounds, at a lower concentration of 50 µg/ml, significantly reduced the aromatase concentration in the ovarian tissues as compared to the untreated control. Collectively, the in silico and in vivo findings recommend that procyanidin B2 and luteolin could be used as potential aromatase inhibitors for overcoming infertility in PCOS patients with estrogen dominance. Communicated by Ramaswamy H. Sarma

Computational studies and structural insights for discovery of potential natural aromatase modulators for hormone-dependent breast cancer.

The aromatase enzyme plays an important role in the progress of hormone-dependent breast cancer, especially in estrogen receptor-positive (ER+) breast cancers. In case of postmenopausal women, the aromatization of androstenedione to estrone in adipose tissue is the most important source of estrogen. Generally 60%-75% of pre- and post-menopausal women suffer from estrogen-dependent breast cancer, and thus suppressing estrogen has been recognized to be a successful therapy. Hence, to limit the stimulation of estrogen, aromatase inhibitors (AIs) are used in the second-line treatment of breast cancer. The present computational study employed an in silico approach in the identification of natural actives targeting the aromatase enzyme from a structurally diverse set of natural products. Molecular docking, QSAR studies and pharmacophore modeling were carried out using the VLife Molecular Design Suite (version 4.6). The stability of the compounds was confirmed by molecular dynamics. From molecular docking and analysis of interactions with the amino acid residues of the binding cavity, it was found that the amino acid residues interacting with the non-steroidal inhibitors exhibited π-stacking interactions with PHE134, PHE 221, and TRP 224, while the steroidal drug exemestane lacked π-stacking interactions. QSAR studies were performed using the flavonoid compounds, in order to identify the structural functionalities needed to improve the anti-breast cancer activity. Molecular dynamics of the screened hits confirmed the stability of compounds with the target in the binding cavity. Moreover, pharmacophore modelling presented the pharmacophoric features of the selected scaffolds for aromatase inhibitory activity. The results presented 23 hit compounds that can be developed as anti-breast cancer modulating agents in the near future. Additionally, anthraquinone compounds with minor structural modification can also serve to be potential aromatase inhibitors. The in silico protocol utilised can be useful in the drug discovery process for development of new leads from structurally diverse set of natural products that are comparable to the drugs used clinically in breast cancer therapy.

Quantum DFT analysis and molecular docking investigation of various potential breast cancer drugs.

Breast cancer is among the deadliest cancers worldwide, highlighting the urgent need for effective treatments. This study employs density functional theory (DFT) and molecular docking analyses to evaluate the anti-cancer efficacy and specificity of drug molecules lapatinib, tucatinib, neratinib, anastrozole, and letrozole. DFT analysis provides comprehensive insights into the structural, electronic, optical, and vibrational properties of these drugs, helping to elucidate their molecular stability and reactivity through global reactivity descriptors. Additionally, molecular docking simulations reveal the binding conformations and interaction profiles of these drugs with key breast cancer targets, underscoring their therapeutic potential. Docking results indicate that lapatinib, tucatinib, and neratinib have high binding affinities for HER2, with lapatinib exhibiting the strongest overall binding, particularly with PDK1 (PDB ID: 1UU7), PAK4 (PDB ID: 2X4Z), GSK3 (PDB ID: 1GNG), and HER2 (PDB ID: 2IOK). The stable hydrogen bonding and other interactions observed with lapatinib support its effectiveness in treating HER2-positive breast cancers, tucatinib's selective HER2 binding reduces off-target effects, while neratinib's irreversible binding provides prolonged inhibition, making it useful for overcoming resistance in HER2-positive cases. In contrast, anastrozole and letrozole show lower binding affinities for HER2 and EGFR due to their simpler structures but are potent aromatase inhibitors, making them effective in treating estrogen receptor-positive (ER-positive) breast cancers. In conclusion, DFT and molecular docking studies affirm the suitability of lapatinib, tucatinib, and neratinib for HER2-positive cancers, while anastrozole and letrozole are effective in ER-positive cancers, emphasizing the role of molecular structure and binding affinity in optimizing cancer treatment strategies.

Design, synthesis, molecular docking and in vitro anticancer activities of 1-(4-(benzamido)phenyl)-3-arylurea derivatives.

In both premenopausal and postmenopausal women, oestrogens play a critical role in the development of breast cancer. Aromatase is an enzyme that catalyses the final step in the biosynthesis of estrogen and has emerged as a promising target for therapeutic intervention. This study aimed to design and evaluate novel 1-(4-(benzamido)phenyl)-3-arylurea derivatives as potential aromatase inhibitors. Through molecular docking, promising leads were identified and synthesized. Spectroscopic techniques confirmed their structural integrity. Cytotoxicity against various cancer cell lines was assessed using MTT assay. Docking investigations against the aromatase enzyme (3s7s) elucidated binding interactions and energies. Compound 6g, exhibiting a binding energy of -8.6 kcal mol-1 and interacting with ALA306 and THR310 residues, showed the most promising activity. It demonstrated GI50 values ranging from 14.46 μM, 13.97 μM, 11.35 μM, 11.58 μM, and 15.77 μM against A-498, NCI-H23, MDAMB-231, MCF-7, and A-549 respectively. Lastly, the physicochemical, and ADMET properties of the compound were predicted. These findings highlight the potential of 1-(4-(benzamido)phenyl)-3-arylureas as a new class of antitumor agents targeting aromatase. Their versatility and superior activity compared to standard chemotherapeutic agents, like doxorubicin, warrant further investigation for the development of broader-spectrum anticancer drugs.

A Computational Exploration: Docking Analysis of Compounds from Foeniculum vulgare as Potential Aromatase Inhibitors for Endometriosis Candidate Therapy

Aromatase inhibitors (AI) have controlling symptoms and size of endometriotic implants, making them a promising second-line therapy for endometriosis treatment.pretreatment with letrozole, an AI, combined with leuprolide acetate and resveratrol has been found to improve in vitro fertilization (IVF) outcomes in women mild endometriosis.in this study we screening and analysis of ten phenolic compounds from Foeniculum vulgare using molecular docking with Mcole server.from this results showed that three phenolic trans resveratrol (TR), caempherol coumaril (CC) have low gibbs energy compare with resveratrol (R). The binding modalities of compound TR and compound R were hydrogen-bonding between the hydroxyl and oxygen atom and Thr310 and hydrophobic interactions with Phe187, Ala272, Asp275, Ala189.and compound R exhibited cation-π interactions between Val336 as binding activity from aromatase.aromatase inhibitors and resveratrolfrom fennel lies in the potential of resveratrol to modulate hormonal pathways, including aromatase inhibition.

Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase.

Estrogen deficiency derived from inhibition of estrogen biosynthesis is a typical condition of postmenopausal women and breast cancer (BCs) patients undergoing antihormone therapy. The ensuing increase in aldosterone levels is considered to be the major cause for cardiovascular diseases (CVDs) affecting these patients. Since estrogen biosynthesis is regulated by aromatase (CYP19A1), and aldosterone biosynthesis is modulated by aldosterone synthase (CYP11B2), a dual inhibitor would allow the treatment of BC while reducing the cardiovascular risks typical of these patients. Moreover, this strategy would help overcome some of the disadvantages often observed in single-target or combination therapies. Following an in-depth analysis of a library of synthesized benzylimidazole derivatives, compound X21 was found to be a potent and selective dual inhibitor of aromatase and aldosterone synthase, with IC50 values of 2.3 and 29 nM, respectively. Remarkably, the compound showed high selectivity with respect to 11β-hydroxylase (CYP11B1), as well as CYP3A4 and CYP1A2. When tested in cells, X21 showed potent antiproliferative activity against BC cell lines, particularly against the ER+ MCF-7 cells (IC50 of 0.26 ± 0.03 μM at 72 h), and a remarkable pro-apoptotic effect. In addition, the compound significantly inhibited mTOR phosphorylation at its IC50 concentration, thereby negatively modulating the PI3K/Akt/mTOR axis, which represents an escape for the dependency from ER signaling in BC cells. The compound was further investigated for cytotoxicity on normal cells and potential cardiotoxicity against hERG and Nav1.5 ion channels, demonstrating a safe biological profile. Overall, these assays demonstrated that the compound is potent and safe, thus constituting an excellent candidate for further evaluation.

New 1,2,3-Triazole/1,2,4-triazole Hybrids as Aromatase Inhibitors: Design, Synthesis, and Apoptotic Antiproliferative Activity.

A novel series of 1,2,3-triazole/1,2,4-triazole hybrids 5a, 5b, and 6a-i was designed and synthesized as antiproliferative agents targeting aromatase enzymes. The antiproliferative activity of the new hybrids against four cancer cells was studied using Erlotinib as a control. Compounds 6a and 6b demonstrated the highest antiproliferative activity among these hybrids, with GI50 values of 40 nM and 35 nM, respectively. Compound 6b was the most potent derivative, with a GI50 of 35 nM, comparable to Erlotinib's GI50 of 33 nM. Compound 6b inhibited all cancer cell lines with comparable efficacy to Erlotinib. Compounds 5a, 5b, and 6a-i were tested for inhibitory action against aromatase as a potential target for their antiproliferative activity. Results revealed that compounds 6a and 6b were the most potent aromatase inhibitors, with IC50 values of 0.12 ± 0.01 µM and 0.09 ± 0.01 µM, respectively, being more potent than the reference Ketoconazole (IC50 = 2.6 ± 0.20 µM) but less potent than Letrozole (IC50 = 0.002 ± 0.0002). These findings indicated that compounds 6a and 6b had significant aromatase inhibitory action and are potential antiproliferative candidates. The findings were further linked to molecular docking investigations, which gave models of strong interactions with the aromatase domain for inhibitors with high binding scores.

In-silico and in-vitro study reveals ziprasidone as a potential aromatase inhibitor against breast carcinoma

Aromatase enzyme plays a fundamental role in the development of estrogen receptors, and due to this functionality, the enzyme has gained significant attention as a therapeutic for reproductive disorders and cancer diseases. The currently employed aromatase inhibitors have severe side effects whereas our novel aromatase inhibitor is more selective and less toxic, therefore has greater potential to be developed as a drug. The research framework of this study is to identify a potent inhibitor for the aromatase target by profiling molecular descriptors of the ligand and to find a functional pocket in the target by docking and MD simulations. For assessing cellular and metabolic activities as indicators of cell viability and cytotoxicity, in-vitro studies were performed by using the colorimetric MTT assay. Aromatase activities were determined by a fluorometric method. Cell morphology was assessed by phase-contrast light microscopy. Flow cytometry and Annexin V-FITC/PI staining assay determined cell cycle distribution and apoptosis. This study reports that CHEMBL708 (Ziprasidone) is the most promising compound that showed excellent aromatase inhibitory activity. By using better drug design methods and experimental studies, our study identified a novel compound that could be effective as a high-potential drug candidate against aromatase enzyme. We conclude that the compound ziprasidone effectively blocks the cell cycle at the G1-S phase and induces cancer cell death. Further, in-vivo studies are vital for developing ziprasidone as an anticancer agent. Lastly, our research outcomes based on the results of the in-silico experiments may pave the way for identifying effective drug candidates for therapeutic use in breast cancer.

Ferrozoles: Ferrocenyl derivatives of letrozole with dual effects as potent aromatase inhibitors and cytostatic agents.

In the treatment of hormone-dependent cancers, aromatase inhibitors (AI) are receiving increased attention due to some undesirable effects such as the risk of endometrial cancer and thromboembolism of SERMs (selective estrogen receptor modulators). Letrozole is the most active AI with 99% aromatase inhibition. Unfortunately, this compound also exhibits some adverse effects such as hot flashes and fibromyalgias. Therefore, there is an urgent need to explore new types of AIs that retain the same-or even increased-antitumor ability. Inspired by the letrozole structure, a set of new derivatives has been synthesized that include a ferrocenyl moiety and different heterocycles. The derivative that contains a benzimidazole ring, namely compound 6, exhibits a higher aromatase inhibitory activity than letrozole and it also shows potent cytostatic behavior when compared to other well-established aromatase inhibitors, as demonstrated by dose-response, cell cycle, apoptosis and time course experiments. Furthermore, 6 promotes the inhibition of cell growth in both an aromatase-dependent and -independent fashion, as indicated by the study of A549 and MCF7 cell lines. Molecular docking and molecular dynamics calculations on the interaction of 6 or letrozole with the aromatase binding site revealed that the ferrocene moiety increases the van der Waals and hydrophobic interactions, thus resulting in an increase in binding affinity. Furthermore, the iron atom of the ferrocene fragment can form a metal-acceptor interaction with a propionate fragment, and this results in a stronger coupling with the heme group-a possibility that is consistent with the strong aromatase inhibition of 6.

Switching from Aromatase Inhibitors to Dual Targeting Flavonoid-Based Compounds for Breast Cancer Treatment

Despite the significant outcomes attained by scientific research, breast cancer (BC) still represents the second leading cause of death in women. Estrogen receptor-positive (ER+) BC accounts for the majority of diagnosed BCs, highlighting the disruption of estrogenic signalling as target for first-line treatment. This goal is presently pursued by inhibiting aromatase (AR) enzyme or by modulating Estrogen Receptor (ER) α. An appealing strategy for fighting BC and reducing side effects and resistance issues may lie in the design of multifunctional compounds able to simultaneously target AR and ER. In this paper, previously reported flavonoid-related potent AR inhibitors were suitably modified with the aim of also targeting ERα. As a result, homoisoflavone derivatives 3b and 4a emerged as well-balanced submicromolar dual acting compounds. An extensive computational study was then performed to gain insights into the interactions the best compounds established with the two targets. This study highlighted the feasibility of switching from single-target compounds to balanced dual-acting agents, confirming that a multi-target approach may represent a valid therapeutic option to counteract ER+ BC. The homoisoflavone core emerged as a valuable natural-inspired scaffold for the design of multifunctional compounds.

An Exemestane Derivative, Oxymestane-D1, as a New Multi-Target Steroidal Aromatase Inhibitor for Estrogen Receptor-Positive (ER+) Breast Cancer: Effects on Sensitive and Resistant Cell Lines.

Around 70-85% of all breast cancer (BC) cases are estrogen receptor-positive (ER+). The third generation of aromatase inhibitors (AIs) is the first-line treatment option for these tumors. Despite their therapeutic success, they induce several side effects and resistance, which limits their efficacy. Thus, it is crucial to search for novel, safe and more effective anti-cancer molecules. Currently, multi-target drugs are emerging, as they present higher efficacy and lower toxicity in comparison to standard options. Considering this, this work aimed to investigate the anti-cancer properties and the multi-target potential of the compound 1α,2α-epoxy-6-methylenandrost-4-ene-3,17-dione (Oxy), also designated by Oxymestane-D1, a derivative of Exemestane, which we previously synthesized and demonstrated to be a potent AI. For this purpose, it was studied for its effects on the ER+ BC cell line that overexpresses aromatase, MCF-7aro cells, as well as on the AIs-resistant BC cell line, LTEDaro cells. Oxy reduces cell viability, impairs DNA synthesis and induces apoptosis in MCF-7aro cells. Moreover, its growth-inhibitory properties are inhibited in the presence of ERα, ERβ and AR antagonists, suggesting a mechanism of action dependent on these receptors. In fact, Oxy decreased ERα expression and activation and induced AR overexpression with a pro-death effect. Complementary transactivation assays demonstrated that Oxy presents ER antagonist and AR agonist activities. In addition, Oxy also decreased the viability and caused apoptosis of LTEDaro cells. Therefore, this work highlights the discovery of a new and promising multi-target drug that, besides acting as an AI, appears to also act as an ERα antagonist and AR agonist. Thus, the multi-target action of Oxy may be a therapeutic advantage over the three AIs applied in clinic. Furthermore, this new multi-target compound has the ability to sensitize the AI-resistant BC cells, which represents another advantage over the endocrine therapy used in the clinic, since resistance is a major drawback in the clinic.

Design and Synthesis of Imidazole Derivatives as Anticancer Agents and Potential Aromatase Inhibitors

In this study, imidazole derivative compounds were synthesized using the Debus-Radziszewski method. The chemical structures of the compounds were characterized by spectroscopic methods. The effects of target compounds on MCF7 (CRL-3435) were examined and their IC50 values and percent viability were calculated. In addition, the cytotoxic effects on the L929 (CCL-1) normal cell line were evaluated in order to determine the selectivities of the compounds. Then, the inhibition values of aromatase enzyme of the compounds were calculated and compared to the reference compound. When the results were examined, it was observed that Compound la caused the death of breast cancer cells, although not as much as cisplatin, but did not harm healthy cells. In this respect, it was determined that compound Ia has a promising anticancer effect as an aromatase inhibitor.

ENCAPSULATION OF EXEMESTANE WITH β-CYCLODEXTRIN AND TERNARY AGENT: FORMULATION, EVALUATION AND ANTICANCER ACTIVITY

Objective: A potent aromatase inhibitor, Exemestane, is well known for its anticancer action in breast neoplasm. The vital problem of this medicament is its poor aqueous solubility, which hinders its dissolution in body fluids. Therefore, the present study targets to enhance the water solubility of Exemestane by means of its complexation with β-cyclodextrin and a suitable ternary agent. Methods: Inclusion complexes of Exemestane with β-cyclodextrin and ternary agent were prepared by kneading and lyophilization technique. Different hydrophilic polymers and organic acids were screened for their influential ability as a co-complex with a carrier; β-cyclodextrin. The validation of complex formation was carried out by various solid-state techniques. The geometry of Exemestane in the β-cyclodextrin cavity was picturized in docking studies. The in vitro anticancer activity of prepared inclusion complex formulations carried out using MCF-7 cell lines Results: Phase solubility analysis proved HPMC E5 as the best ternary agent for complexation of Exemestane with β-cyclodextrin as it improved the stability constant of the drug from 665.92 M-1 to 1238.38 M-1. The synthesized binary and ternary inclusion complexes exhibited 2.74 and 4.62 times enhanced solubilization of Exemestane. Likewise, the dissolution characteristics of Exemestane were improved, and drug release was increased by 1.18 and 1.42 times with binary and ternary freeze-dried formulations. Differential scanning calorimetry (DSC) and powder X-ray diffractometry (PXRD) study results presented the formation of binary and ternary complexes with significantly drooped crystallinity. Docking studies predicted encapsulation of rings A, B, and C of Exemestane in the cavity of β-cyclodextrin. In-line results were obtained in Fourier transform infrared (FTIR) studies. The cell growth inhibition of 62.78 % was achieved with a ternary complex of Exemestane which was far superior than the pure active moiety that showed mere 44.56 % of inhibition. Conclusion: Altogether, it can be concluded that the inclusion complex of Exemestane boosted its aqueous solubility, resulting in its increased dissolution and in vitro anticancer activity in a breast cancer MCF-7 cell line.