RESUMEN
Breast cancer remains a major global health issue, particularly affecting women and contributing significantly to mortality rates. Current treatments for estrogen receptor-positive breast cancers, such as aromatase inhibitors, are effective but often come with side effects and resistance issues. This study addresses these gaps by targeting aromatase, an enzyme crucial for estrogen synthesis, which plays a pivotal role in breast cancer progression. The innovative approach involves synthesizing novel bis-triazolopyridopyrimidines, designed to leverage the combined pharmacological benefits of pyridopyrimidine and 1,2,4-triazole structures, known for their potent aromatase inhibition and anti-cancer properties. These compounds were synthesized and characterized using 1H-NMR, 13C-NMR, and MS spectral analyses, and their anticancer efficacy was evaluated through MTT assays against MCF-7 breast cancer cell lines inâ vitro. Molecular docking analyses revealed strong binding energies with aromatase, particularly for compounds 5 b, 5 c, 10 a, and 10 b, indicating their potential as effective aromatase inhibitors. The study highlights these compounds as promising candidates for further development as therapeutic agents against breast cancer.
Asunto(s)
Antineoplásicos , Inhibidores de la Aromatasa , Aromatasa , Curcumina , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular , Pirimidinas , Humanos , Inhibidores de la Aromatasa/farmacología , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/química , Aromatasa/metabolismo , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Células MCF-7 , Curcumina/farmacología , Curcumina/química , Curcumina/síntesis química , Curcumina/análogos & derivados , Estructura Molecular , Proliferación Celular/efectos de los fármacos , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Relación Dosis-Respuesta a Droga , Supervivencia Celular/efectos de los fármacosRESUMEN
Estrogen receptor α (ERα) plays a pivotal role in the proliferation, differentiation, and migration of breast cancer (BC) cells, and aromatase (ARO) is a crucial enzyme in estrogen synthesis. Hence, it is necessary to inhibit estrogen production or the activity of ERα for the treatment of estrogen receptor-positive (ER+) BC. Herein, we present a new category of dual-targeting PROTAC degraders designed to specifically target ERα and ARO. Among them, compound 18c bifunctionally degrades and inhibits ERα/ARO, thus effectively suppressing the proliferation of MCF-7 cells while showing negligible cytotoxicity to normal cells. In vivo, 18c promotes the degradation of ERα and ARO and inhibits the growth of MCF-7 xenograft tumors. Finally, compound 18c demonstrates promising antiproliferative and ERα degradation activity against the ERαMUT cells. These findings suggest that 18c, being the inaugural dual-targeting degrader for ERα and ARO, warrants further advancement for the management of BC and the surmounting of endocrine resistance.
Asunto(s)
Neoplasias de la Mama , Proliferación Celular , Resistencia a Antineoplásicos , Receptor alfa de Estrógeno , Humanos , Receptor alfa de Estrógeno/metabolismo , Receptor alfa de Estrógeno/antagonistas & inhibidores , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Femenino , Animales , Resistencia a Antineoplásicos/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ratones , Aromatasa/metabolismo , Inhibidores de la Aromatasa/farmacología , Inhibidores de la Aromatasa/química , Inhibidores de la Aromatasa/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Células MCF-7 , Proteolisis/efectos de los fármacos , Ratones Desnudos , Descubrimiento de Drogas , Relación Estructura-ActividadRESUMEN
A series of enantioenriched ß-indolyl ketones as aromatase inhibitors (AI) is synthesized through the Michael-type Friedel-Crafts alkylation of indole. A highly efficient bifunctionalized amino catalyst is developed to access structurally diverse ß-indolyl ketones in high yields (up to 91%) and excellent enantioselectivity (enantiomeric ratio up to 98:2). All the synthesized compounds demonstrated promising aromatase inhibitory potential, where ortho-substituted analogs (3c and 3e) were found most active with IC50 values of 0.68 and 0.90 µM, respectively. Both of these compounds exhibited significant cytotoxicity (IC50 = 0.34 and 0.37 µM) against the MCF-7 breast cancer cell line in the (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay. Molecular docking studies of the synthesized compounds demonstrate favorable binding interactions with the estrogens controlling CYP19A1 (3EQM) and metabolizing CYP3A4 (5VCC) enzymes. Molecular dynamic (MD) simulation analysis revealed the essentiality of heme-ligand interactions to build a stable protein-ligand complex. An average root mean square deviation of 0.35 nm observed during a 100-ns MD simulation and binding free energy in the range of -190 to -227 kJ/mol calculated by g_mmpbsa analysis authenticated the stability of the 3c-3EQM complex. ADMET and drug-likeness parameters supported the suitability of these indole derivatives as the drug lead to develop potent inhibitors for estrogen-dependent breast cancer.
Asunto(s)
Inhibidores de la Aromatasa , Aromatasa , Indoles , Cetonas , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Humanos , Indoles/farmacología , Indoles/química , Indoles/síntesis química , Ligandos , Cetonas/farmacología , Cetonas/química , Cetonas/síntesis química , Inhibidores de la Aromatasa/farmacología , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/química , Células MCF-7 , Relación Estructura-Actividad , Aromatasa/metabolismo , Estereoisomerismo , Hemo/metabolismo , Hemo/química , Estructura Molecular , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos AntitumoralesRESUMEN
Background: 4-Methylacetophenone is used 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 were investigated for their cytotoxic activity on MCF-7 and normal breast cells. Active compounds were found and in 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.
[Box: see text].
Asunto(s)
Antineoplásicos , Inhibidores de la Aromatasa , Neoplasias de la Mama , Tiazoles , Humanos , Tiazoles/química , Tiazoles/farmacología , Tiazoles/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Inhibidores de la Aromatasa/farmacología , Inhibidores de la Aromatasa/química , Inhibidores de la Aromatasa/síntesis química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Femenino , Relación Estructura-Actividad , Ensayos de Selección de Medicamentos Antitumorales , Proliferación Celular/efectos de los fármacos , Aromatasa/metabolismo , Células MCF-7 , Estructura MolecularRESUMEN
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.
Asunto(s)
Inhibidores de la Aromatasa , Aromatasa , Neoplasias de la Mama , Diseño de Fármacos , Receptor alfa de Estrógeno , Flavonoides , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/metabolismo , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/química , Inhibidores de la Aromatasa/farmacología , Flavonoides/síntesis química , Flavonoides/química , Flavonoides/farmacología , Humanos , Femenino , Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor alfa de Estrógeno/química , Receptor alfa de Estrógeno/metabolismo , Simulación de Dinámica Molecular , Aromatasa/química , Aromatasa/metabolismo , Termodinámica , Concentración 50 Inhibidora , Simulación del Acoplamiento MolecularRESUMEN
The inhibitory effects of 2-thiazolyl hydrazones on monoamine oxidase enzymes are known for a long time. In this study, a new series of 2-thiazolyl hydrazone derivatives were synthesized starting from 6-methoxy-2-naphthaldehyde. All of the synthesized compounds were investigated in terms of their monoamine oxidase (MAO) inhibitory effects and significant results were found. The results showed that compound 2j potently inhibited MAO-A and MAO-B, while compound 2t strongly and selectively inhibited MAO-B compared to standard drugs. Compounds 2k and 2q exhibited selective and satisfying inhibition on MAO-B. In the aromatase inhibition studies of the compounds, it was determined that compounds 2q and 2u had high inhibitory properties. Molecular docking studies on MAO-A, MAO-B, and aromatase enzymes were carried out for the aforementioned compounds. Additionally, molecular dynamics simulation was studied for compound 2q on MAO-B and aromatase complexes. Finally, the Field-based QSAR study was developed and the structure-activity relationship (SAR) was explained. For the first time, dual inhibitors on MAO and aromatase enzyme were investigated together. The aim of this approach is for finding the potential agents that do not cause the cognitive disorders and may even treat neurodegenerative symptoms, thus, the aim was reached successfully.
Asunto(s)
Inhibidores de la Aromatasa/síntesis química , Aromatasa/metabolismo , Hidrazonas/síntesis química , Inhibidores de la Monoaminooxidasa/síntesis química , Monoaminooxidasa/metabolismo , Inhibidores de la Aromatasa/farmacología , Evaluación Preclínica de Medicamentos , Humanos , Hidrazonas/farmacología , Simulación del Acoplamiento Molecular , Inhibidores de la Monoaminooxidasa/farmacología , Unión Proteica , Conformación Proteica , Relación Estructura-ActividadRESUMEN
Nonsteroidal aromatase inhibitors (NSAIs) are well-established drugs for the therapy of breast cancer. However, they display some serious side effects, and their efficacy can be compromised by the development of chemoresistance. Previously, we have reported different indazole-based carbamates and piperidine-sulphonamides as potent aromatase inhibitors. Starting from the most promising compounds, here we have synthesised new indazole and triazole derivatives and evaluated their biological activity as potential dual agents, targeting both the aromatase and the inducible nitric oxide synthase, being this last dysregulated in breast cancer. Furthermore, selected compounds were evaluated as antiproliferative and cytotoxic agents in the MCF-7 cell line. Moreover, considering the therapeutic diversity of azole-based compounds, all the synthesized compounds were also evaluated as antifungals on different Candida strains. A docking study, as well as molecular dynamics simulation, were carried out to shed light on the binding mode of the most interesting compound into the different target enzymes catalytic sites.
Asunto(s)
Antifúngicos/farmacología , Antineoplásicos/farmacología , Inhibidores de la Aromatasa/farmacología , Compuestos Azo/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Simulación del Acoplamiento Molecular , Micosis/tratamiento farmacológico , Antifúngicos/síntesis química , Antifúngicos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/química , Compuestos Azo/síntesis química , Compuestos Azo/química , Candida/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Herein, we present the synthesis and crystal structures determination of five 4-(1-phenyl-1H-1,2,3-triazol-4-yl)phenol derivatives containing halogen atoms, 6a-e, which may be used as an excellent mimic of steroids in the drug development process. Good quality crystals obtained for all of the synthesized compounds allowed the analysis of their molecular structures. Subsequently, the determined crystal structures were used to calculate the Hirshfeld surfaces for each of the synthesized compounds. Furthermore, results of our docking studies indicated that synthesized derivatives are able to bind effectively to the active sites of selected enzymes and receptors involved in the hormone biosynthesis and signaling pathways, analogously to the native steroids.
Asunto(s)
Inhibidores de la Aromatasa/síntesis química , Simulación del Acoplamiento Molecular , Triazoles/síntesis química , Aromatasa/química , Aromatasa/metabolismo , Inhibidores de la Aromatasa/farmacología , Dominio Catalítico , Cristalización , Halógenos/química , Fenoles/química , Unión Proteica , Triazoles/farmacologíaRESUMEN
Aromatase inhibitors used against hormone-dependent breast cancer, especially in post-menopausal women, are very susceptible to the development of resistance due to their limited number and long-term use. In this study, it is aimed to obtain new aromatase inhibitors including thiazole and dihydrofuran ring systems. Synthesis of compounds (2a-2l) were performed according to literature methods. Their structures were elucidated by 1H NMR, 13C NMR and APCI-MS spectroscopic methods. MTT test was carried out to assess the cell proliferation effects of the different compounds on two different pulmonary cell lines (A549, CCD-19Lu) and mammary cell line (MCF7). According to MTT assay, it was observed that the calculated IC50 values of some compounds for the CCD-19Lu cell line were found higher than for the A549 and MCF7 cell lines. Considering the viability results, it was found that the selected compounds (2a, 2c, 2e, 2g, 2h, 2l) showed favourable safety profile and have anticancer activities. Apoptotic activities of the selected compounds were investigated by flow cytometry analysis. And were found that have apoptotic effects on cancerous cell lines. In the light of this information, the aromatase inhibition potentials of 2g and 2l compounds, which are the most active derivatives, were examined in vitro and it was determined that they showed a similar inhibition profile with letrazole. Interaction modes between aromatase enzyme and compounds 2g and 2l were investigated by docking studies. In conclusion, findings of these study indicate that compounds 2g and 2l possess significant anticancer activity.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de la Aromatasa/farmacología , Aromatasa/metabolismo , Diseño de Fármacos , Furanos/farmacología , Tiazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Furanos/química , Humanos , Estructura Molecular , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
Bismuth(iii)-catalyzed regioselective functionalization at the C-6 position of tetrahydroquinolines and the C-5 position of indolines has been demonstrated. For the first time, one pot symmetrical and unsymmetrical arylation of isatins with tetrahydroquinolines was accomplished giving a completely new product skeleton in good to excellent yields. Most importantly, this protocol leads to the formation of a highly strained quaternary carbon stereogenic center, which is a challenging task. Benzhydryl and 1-phenylethyl trichloroacetimidates have been used as the alkylating partners to functionalize the C-6 and C-5 positions of tetrahydroquinolines and indolines, respectively. The scope of the developed methodology has been extended for the synthesis of the bioactive CYP19-inhibitor and its analogue.
Asunto(s)
Inhibidores de la Aromatasa/síntesis química , Aromatasa/metabolismo , Bismuto/química , Hidroquinonas/química , Oxindoles/química , Alquilación , Inhibidores de la Aromatasa/química , Catálisis , Técnicas de Química Sintética , Isatina/química , Oxindoles/síntesis química , EstereoisomerismoRESUMEN
BACKGROUND: It takes a lot more studies to evaluate the molecular interaction of nanoparticles with the drug, their drug delivery potential and release kinetics. Thus, we have taken in silico and in vitro approaches into account for the evaluation of the drug delivery ability of the chitosan nanoparticles. OBJECTIVE: The present work was aimed to study the interaction of chitosan nanoparticles with appropriate aromatase inhibitors using in silico tools. Further, synthesis and characterization of chitosan nanoparticles having optimal binding energy and affinity between drug and polymer in terms of size, encapsulation efficiency were carried out. METHODS: In the current study, molecular docking was used to map the molecular interactions and estimation of binding energy involved between the nanoparticles and the drug molecules in silico. Letrozole is used as a model cytotoxic agent currently being used clinically; hence Letrozole loaded chitosan nanoparticles were formulated and characterized using photomicroscope, particle size analyzer, scanning electron microscope and fourier transform infra-red spectroscopy. RESULTS: Letrozole had the second-highest binding affinity within the core of chitosan with MolDock (-102.470) and Re-rank (-81.084) scores. Further, it was investigated that formulated nanoparticles were having superior drug loading capacity and high encapsulation efficiency. In vitro drug release study exhibited prolonged release of the drug from chitosan nanoparticles. CONCLUSION: Results obtained from the in silico and in vitro studies suggest that Letrozole loaded nanoparticles are ideal for breast cancer treatment.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de la Aromatasa/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Letrozol/farmacología , Simulación del Acoplamiento Molecular , Nanopartículas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/química , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Quitosano/química , Quitosano/farmacología , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Letrozol/síntesis química , Letrozol/química , Estructura Molecular , Polímeros/química , Polímeros/farmacología , Relación Estructura-ActividadRESUMEN
BACKGROUND: Aromatase, a cytochrome P450 hemoprotein that is responsible for estrogen biosynthesis by conversion of androgens into estrogens, has been an attractive target in the treatment of hormonedependent breast cancer. Design of new steroidal aromatase inhibitors becomes imperative. OBJECTIVE: Synthesis and biological evaluation of two classes of structurally and functionally diverse D-ring pregnenolone pyrazoles as type I aromatase inhibitors and antiproliferative agents. METHODS: Pregnenolone (1) was converted to 3ß-hydroxy-21-hydroxymethylidenepregn-5-en-20-one (2), which upon cyclization with phenylhydrazine generated regioisomeric pairs of pyrazoles 4 and 5. Further, Knoevenagel condensation of pregnenolone (1) with 3-oxo-3-phenylpropanenitrile (6) produced 2-benzoyl-3-(3b-hydroxyandrostan- 5-ene-20-ylidene)-but-2-enenitrile (7), which upon cyclization with hydrazine or phenylhydrazine generated the pyrazoles 8 and 9. All new steroidal derivatives were tested for their aromatase inhibition activity using Dibenzylfluorescein (DBF) based fluorescence assay developed by Stresser et al. Antiproliferative activities were measured using Sulforhodamine B assay. The activities were promising and there was a coherence between aromatase inhibitory and antiproliferative activities. RESULTS: The study reveals the immense potential of pregnenolone pyrazoles as aromatase inhibitors for the treatment of breast cancer. Molecular docking studies proved efficient binding of the new steroidal analogs on human placental aromatase. CONCLUSION: In the overall study, most of the compounds exhibited potential activity for the treatment of hormone dependent breast cancer. Compounds 4c and 4d were found to be the most promising pharmacons. Furthermore, compounds 4c and 4d were applied for their molecular docking study on human placental aromatase to predict their possible binding modes with the enzyme. These studies revealed that such molecules have high scope and potential for further investigation towards the treatment of estrogen dependent breast cancer.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de la Aromatasa/farmacología , Aromatasa/metabolismo , Pregnenolona/farmacología , Pirazoles/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/química , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Modelos Moleculares , Estructura Molecular , Pregnenolona/síntesis química , Pregnenolona/química , Pirazoles/síntesis química , Pirazoles/química , Células Tumorales CultivadasRESUMEN
In the search for novel aromatase inhibitors, a series of triazole and imidazole-based carbamate derivatives were designed and synthesized. Final compounds were thus evaluated against human aromatase by in vitro kinetic experiments in a fluorimetric assay in comparison with letrozole. The effect of most active derivatives 13a and 15c was then evaluated in vitro on the human breast cancer cell line MCF7 by MTT assay, cytotoxicity assay (LDH release) and cell cycle analysis, revealing a dose-dependent inhibition profile of cell viability and low micromolar IC50 values. In addition, docking simulations were also carried out to elucidate at a molecular level of detail the binding modes adopted to target human aromatase.
Asunto(s)
Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/uso terapéutico , Carbamatos/síntesis química , Carbamatos/uso terapéutico , Imidazoles/síntesis química , Imidazoles/uso terapéutico , Triazoles/síntesis química , Triazoles/uso terapéutico , Inhibidores de la Aromatasa/farmacología , Carbamatos/farmacología , Diseño de Fármacos , Humanos , Imidazoles/farmacología , Estructura Molecular , Triazoles/farmacologíaRESUMEN
Inhibition of aromatase enzymes is very important in the prevention of estrogen-related diseases and the regulation of estrogen levels. Aromatase enzyme is involved in the final stage of the biosynthesis of estrogen, in the conversion of androgens to estrogen. The development of new compounds for the inhibition of aromatase enzymes is an important area for medicinal chemists in this respect. In the present study, new benzimidazole derivatives have been designed and synthesized which have reported anticancer activity in the literature. Their anticancer activity was evaluated against human A549 and MCF-7 cell lines by MTT assay. In the series, concerning MCF-7 cell line, the most potent compounds were the 4-benzylpiperidine derivatives 2c, 2g, and 2k with IC50 values of 0.032 ± 0.001, 0.024 ± 0.001, and 0.035 ± 0.001 µM, respectively, compared to the reference drug cisplatin (IC50 = 0.021 ± 0.001 µM). Then, these compounds were subject to further in silico aromatase enzyme inhibition assays to determine the possible binding modes and interactions underlying their activity. Thanks to molecular docking studies, the effectiveness of these compounds against aromatase enzyme could be simulated. Consequently, it has been found that these compounds can be settled very properly to the active site of the aromatase enzyme.
Asunto(s)
Antineoplásicos/síntesis química , Inhibidores de la Aromatasa/síntesis química , Aromatasa/química , Bencimidazoles/síntesis química , Células A549 , Antineoplásicos/química , Antineoplásicos/farmacología , Aromatasa/metabolismo , Inhibidores de la Aromatasa/química , Inhibidores de la Aromatasa/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Dominio Catalítico/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Humanos , Células MCF-7 , Modelos Moleculares , Conformación Molecular , Simulación del Acoplamiento Molecular , Relación Estructura-ActividadRESUMEN
BACKGROUND: Estrogens are essential for the growth of breast cancer in the case of premenopausal as well as in postmenopausal women. However, most of the breast cancer incidences are reported in postmenopausal women and the concurrent risk surges with an increase in age. Since the enzyme aromatase catalyses essential steps in estrogen biosynthesis, Aromatase Inhibitors (AIs) are effective targeted therapy in patients with Estrogen Receptor positive (ER+) breast cancer. AIs are more effective than Selective Estrogen Receptor Modulators (SERMs) because they block both the genomic and nongenomic activities of ER. Till date, first, second and third-generation AIs have been approved by the FDA. The third-generation AIs, viz. Letrozole, Anastrozole, Exemestane, are currently used in the standard treatment for postmenopausal breast cancer. METHODS: Data were collected from Medline, PubMed, Google Scholar, Science Direct through searching of keywords: 'aromatase', 'aromatase inhibitors', 'breast cancer', 'steroidal aromatase inhibitors', 'non-steroidal inhibitors' and 'generations of aromatase inhibitors'. RESULTS: In the current scenario of breast cancer chemotherapy, AIs are the most widely used agents which reveal optimum efficacy along with the least side effects. Keeping in view the prominence of AIs in breast cancer therapy, this review covered the detailed description of aromatase including its role in the biosynthesis of estrogen, biochemistry, gene expression, 3D-structure, and information of reported AIs along with their role in breast cancer treatment. CONCLUSION: AIs are the mainstream solution of the ER+ breast cancer treatment regimen with the continuous improvement of human understanding of the importance of a healthy life of women suffering from breast cancer.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de la Aromatasa/farmacología , Aromatasa/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/química , Neoplasias de la Mama/enzimología , Femenino , Humanos , Estructura MolecularRESUMEN
The synthesis of new N-(5-substituted-1,3,4-thiadiazol-2-yl)-2-[(5-(substituted amino)-1,3,4-thiadiazol-2-yl)thio]acetamide derivatives and investigation of their anticancer activities were the aims of this work. All the new compounds' structures were elucidated by elemental analyses, IR, 1H NMR, 13C NMR and MS spectral data. Anticancer activity studies of the compounds were evaluated against MCF-7 and A549 tumor cell lines. In addition, with the purpose of determining the selectivity of cytotoxic activities, the most active compound was screened against a noncancer NIH3T3 cell line (mouse embryonic fibroblast cells). Among the tested compounds, compound 4y (N-(5-ethyl-1,3,4-thiadiazol-2-yl)-2-((5-(p-tolylamino)-1,3,4-thiadiazol-2-yl)thio)acetamide), showed promising cytotoxic activity against MCF7 cancer cell with an IC 50value of 0.084 ± 0.020 mmol L-1 and against A549 cancer cell with IC 50 value of 0.034 ± 0.008 mmol L-1, compared with cisplatin. The aromatase inhibitory activity was evaluated for compound 4y on MCF-7 cell line showing promising activity with IC50 of 0.062 ± 0.004 mmol L-1.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Tiadiazoles/síntesis química , Tiadiazoles/farmacología , Células A549 , Animales , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/farmacología , Supervivencia Celular/efectos de los fármacos , Cisplatino/farmacología , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Ratones , Células 3T3 NIH , Relación Estructura-Actividad , Sales de Tetrazolio , TiazolesRESUMEN
In the last step of estrogen biosynthesis, aromatase enzyme catalyzes the conversion of androgens to estrogens. Aromatase inhibition is an important way to control estrogen-related diseases and estrogen levels. In this study, sixteen of benzimidazole-triazolothiadiazine derivatives have been synthesized and studied as potent aromatase inhibitors. First, these compounds were tested for their anti-cancer properties against human breast cancer cell line (MCF-7). The most active compounds 5c, 5e, 5k, and 5m on MCF-7 cell line were subject to further in vitro aromatase enzyme inhibition assays to determine the possible mechanisms of action underlying their activity. Compound 5e showed slight less potent aromatase inhibitory activity than that of letrozole with IC50 = 0.032 ± 0.042 µM, compared to IC50 = 0.024 ± 0.001 µM for letrozole. Furthermore, compound 5e and reference drug letrozole were docked into human placental aromatase enzyme to predict their possible binding modes with the enzyme. Finally, ADME parameters (absorption, distribution, metabolism, and excretion) of synthesized compounds (5a-5p) were calculated by QikProp 4.8 software.
Asunto(s)
Antineoplásicos/síntesis química , Inhibidores de la Aromatasa/síntesis química , Bencimidazoles/síntesis química , Neoplasias Encefálicas/enzimología , Antineoplásicos/química , Antineoplásicos/farmacología , Inhibidores de la Aromatasa/química , Inhibidores de la Aromatasa/farmacología , Bencimidazoles/química , Bencimidazoles/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Humanos , Letrozol/química , Letrozol/farmacología , Células MCF-7 , Simulación del Acoplamiento MolecularRESUMEN
Novel anti-proliferative agents possessing pyrimidine scaffolds were designed, synthesized and evaluated for their IC50 values using MTT assay. Most compounds displayed good to excellent activity against the two tested breast cancer lines (MCF-7 and MDA-MB-231) as compared to 5-FU. The observed IC50 values for active compounds ranged from 0.27 to 10.57 µM in MCF-7 compared to the reference drug 5-FU (IC50 = 10.80 µM) and from 0.73 to 29.07 µM in MDA-MB-231 (IC50 for 5-FU = 11.40 µM). SAR analysis indicated that compounds 2c, 3b with hydrazone functionalities and compound 12 possessing pyrazolone ring exhibited superior activities. The most promising compounds were evaluated for their inhibitory activity against epidermal growth factor receptor (EGFR) and aromatase (ARO) enzymes and were further tested for caspase-9 activation, apoptosis and Annexin V/PI staining. Results of enzyme-based experiments indicated that the tested compounds 2c and 12 exert their activities through EGFR inhibition while compound 3b exhibited remarkable ARO inhibition activity. Furthermore, they remarkably induce caspase-9 activation and showed pre G1 apoptosis and cell cycle arrest at G2/M phase. In addition, docked compounds displayed good binding affinities to the target enzymes. Binding interaction details for the most promising inhibitors with the active site of the target enzymes EGFR and ARO utilizing MOE-dock method are also reported.
Asunto(s)
Compuestos de Anilina/farmacología , Antineoplásicos/farmacología , Inhibidores de la Aromatasa/farmacología , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Compuestos de Anilina/síntesis química , Compuestos de Anilina/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Aromatasa/metabolismo , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/química , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/metabolismo , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Relación Estructura-ActividadRESUMEN
Aromatase is involved in the biosynthesis of estrogen and thus is a critical target for breast cancer. In this study, to identify new aromatase enzyme inhibitors, seven 3-[4-(5-methyl-1H-benzo[d]imidazol-2-yl)phenyl]-6-(substituted phenyl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine derivatives were synthesized. First, a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to determine the inhibitory activity of the synthesized compounds on the MCF-7 cell line. The aromatase inhibitory activity was determined for the active compounds 5b, 5c, 5e, and 5g on the MCF-7 cell line. Compound 5g showed significant aromatase inhibitory activity (IC50 = 0.037 ± 0.001 µM). Interestingly, this compound, which bears a difluoro substituent at positions 2 and 4 of the phenyl ring, displayed the most potent aromatase inhibitory activity without significant cytotoxicity to a normal healthy cell line (NIH3T3). Furthermore, the interactions between the best active compounds and the active site of the enzyme were analyzed through a docking study. The results of this study determined that benzimidazole-triazolothiadiazine derivatives are promising compounds that should be further developed as a novel class of aromatase inhibitors.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de la Aromatasa/farmacología , Bencimidazoles/farmacología , Simulación del Acoplamiento Molecular , Tiadiazinas/farmacología , Células A549 , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Aromatasa , Inhibidores de la Aromatasa/síntesis química , Inhibidores de la Aromatasa/química , Bencimidazoles/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Células MCF-7 , Ratones , Estructura Molecular , Células 3T3 NIH , Relación Estructura-Actividad , Tiadiazinas/químicaRESUMEN
In the present study, a new series of α-Aminophosphonates bearing 6-amino-1,3-dimethyluracil was synthesized in good to excellent yields (78-95%) by one-pot, three-component reaction of 6-amino-1,3-dimethyluracil, aromatic aldehydes and diethylphosphite via Kabachnik-Fields reaction by using an eco-friendly Eaton's reagent. All the compounds were screened for in vitro antioxidant studies by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydrogen peroxide (H2O2) methods. Among the synthesized bioactive molecules, 4a, 4d, 4g, and 4h exhibited promising antioxidant activity compared with the standard drug Ascorbic acid. Furthermore, in order to support the biological results of the compounds, molecular docking studies were performed against Aromatase enzyme for four compounds which revealed that the compounds 4a, 4d, 4g, and 4h have significant binding modes, with docking scores of -8.6, -8.4, -8.1 and -8.1 respectively and the compound 4b specifically has equal dock score of -8.0 when compared with the standard drug Exemestane.