Anti-breast Cancer Compounds Research Articles

Assessments of anti-breast cancer activity and profiling of active compounds using LC-MS/MS from the Indonesian Agelas nakamurai

Breast cancer is now one of the leading causes of death in women worldwide. Finding a cure is, therefore, critical for women’s health. Marine sponge-derived drugs have gained interest in breast cancer treatment. The development of marine natural products into cancer therapy includes several stages. It starts with the screening using the cytotoxic test method, a preclinical trial using the animal mode, and clinical trial phases I and II. In this study, we focus on the basic cytotoxic test to find the new source of anti-breast cancer compounds derived from Agelas nakamurai to know the potential for further investigation to become lead compounds. However, the anti-breast cancer potential of the Indonesian marine sponge A. nakamurai has never been studied. This study aimed to evaluate the anti-breast cancer potential of extract and fraction of A. nakamurai against epithelial human breast cancer cells (MDA-MB-231 and MCF-7 cells line) and to preliminary profile the known active compounds. The maceration using methanol was used for extraction and followed by partitioning with varied solvents [ethyl acetate (EtOAc), butanol, and water]. Fractionation was done using normal phase open column chromatography, and liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) was used for analyzing compounds. MDA-MB-231, MCF-7, and HEK-293 cell lines were used for biological activities. The chromatographic separation of the EtOAc fraction led to the F7 subfraction which strongly inhibits proliferation against the MDA-MD-231 (IC50: 10.677 μg/mL), MCF-7 (IC50: 15.154 μg/mL), and HEK-293 cells line. The LC-MS/MS data of active fraction F7 contained gelatin-D and ageloxime-D. This study reported that fraction 7 of A. nakamurai showed strong activity against MDA-MB-231, MCF-7, and HEK-293 cell lines. Further analysis will be carried out to know the mechanisms of action of active compounds.

In silico design and cell-based evaluation of two dual anti breast cancer compounds targeting Bcl-2 and GPER

According to WHO statistics, breast cancer (BC) disease represents about 2.3 million diagnosed and 685,000 deaths globally. Regarding histological classification of BC, the Estrogen (ER) and Progesterone (PR) receptors negative-expression cancer, named Triple-Negative BC (TNBC), represents the most aggressive type of this disease, making it a challenge for drug discovery. In this context, our research group, applying a well-established Virtual Screening (VS) protocol, in addition to docking and molecular dynamics simulations studies, yielded two ligands identified as 6 and 37 which were chemically synthesized and evaluated on MCF-7 and MDA-MB-231 cancer cell lines. Strikingly, 37 assayed on MDA-MB-231 (a TNBC cell model) depicted an outstanding value of 18.66 μM much lower than 65.67 μM yielded by Gossypol Bcl-2 inhibitor whose main disadvantage is to produce multiple toxic effects. Highlighted above, enforce the premise of the computational tools to find new therapeutic options against the most aggressive forms of breast cancer, as the results herein showed.

Insight into Structure-Activity Relationship of New Compounds for Breast Cancer Treatment.

Breast cancer has always been a vicious disease that threatens female health. Although the existing surgery, radiotherapy, chemotherapy, and kinase-targeted drugs have achieved certain effects, there are still many shortcomings. Novel compounds used to treat breast cancer, particularly TNBC, are eagerly being discovered. More than 100 novel compounds that show anti-breast cancer growth were compiled from public databases. The compound design strategies, structure-activity relationship research, and activity evaluation methods have also been reviewed. These novel anti-breast cancer compounds can be divided into mechanisms of action: kinase inhibitors, epigenetic inhibitors, dual inhibitors, degraders, metal complexes, etc. The design strategies mainly include conformational constraint, scaffold-hopping, merging key pharmacophores, etc. Structure-activity relationship studies of these new compounds mainly focus on increasing activity, improving selectivity, increasing membrane permeability, reducing toxicity, improving pharmacokinetic properties, etc. Conclusion: Through the structural optimization of kinase inhibitors, microtubule-targeted drugs, and metal complexes, it is expected to obtain more advantageous breast cancer treatment drugs. It cannot be ignored that epigenetic inhibitors, dual inhibitors and degraders may bring new breast cancer treatment strategies.

Cholestan Steroids from The Stem Bark of Aglaia angustifolia Miq and Their Cytotoxic Activity against MCF-7 Breast Cancer Cell Lines

With about 120 species, Aglaia is one of the largest genera of the plant family Meliaceae (the mahogany plants). Various Aglaia species have been investigated since the 1960s for their phytochemical constituents and biological properties. This research objective was to find secondary metabolites that have activity as anti-breast cancer compounds from endemic Indonesian Aglaia, such as Aglaia angustifolia Miq. Two cholestan type steroids, stigmast-5en-3α-acetat (1), as a new steroid with α-sterochemistry of acetyl moiety at C-3 and 23a-homostigmast-5en-3β-ol (2), with unusual side chain were isolated for the first time from the stem bark of Aglaia angustifolia Miq or known as segara tree in Kalimantan. The chemical structures of two steroids were identified with spectroscopic data, including IR, NMR (1H, 13C, DEPT 135°, HMQC, HMBC, NOESY, 1H-1H COSY) and HRTOF-MS, as well as by comparing with previously reported spectral data. These two steroids were isolated for the first time from this genus. Steroids 1 and 2 were evaluated for cytotoxic activity against MCF-7 breast cancer cells and showed weak activity with IC50 values of 829.0 and 903.0 µg/mL, respectively.

Structure-based virtual screening of anti-breast cancer compounds from Artemisia absinthium—insights through molecular docking, pharmacokinetics, and molecular dynamic simulations

Breast cancer is the world’s second most frequent malignancy, with a significant mortality and morbidity rate. Nowadays, natural breast cancer medicine has piqued attention as disease-curing agent with low side effects. Herein, the leaf powder of Artemisia absinthium was extracted with ethanol, and GC-MS and LC-MS methods were employed to identify the phytocompounds. Using commercial software SeeSAR-9.2 and StarDrop, identified phytocompounds were docked with estrogen and progesterone breast cancer receptors as they promote breast cancer growth to find the binding affinity of the ligands, drugability, and toxicity. Hormone-mediated breast cancer accounts for about 80% of all cases of breast cancer. Cancer cells proliferate when estrogen and progesterone hormones are attached to these receptors. The molecular docking results demonstrated that 3’,4’,5,7-Tetrahydroxyisoflavanone (THIF) has stronger binding efficacy than standard drugs and other phytocompounds with −28.71 (3 hydrogen bonds) and −24.18 kcal/mol (6 hydrogen bonds) binding energies for estrogen and progesterone receptors, respectively. Pharmacokinetics and toxicity analysis were done to predict the drug-likeness of THIF which results in good drugability and less toxicity. The best fit THIF was subjected to a molecular dynamics simulation analysis by using Gromacs to analyze the conformational changes that occurred during protein-ligand interaction and found that, the structural changes were observed. The results from MD simulation and pharmacokinetic studies suggested that THIF can be expected that in vitro and in vivo research on this compound may lead to the development of a potent anti-breast cancer drug in the future. Communicated by Ramaswamy H. Sarma

Prediction of ADMET Properties of Anti-Breast Cancer Compounds Using Three Machine Learning Algorithms.

In recent years, machine learning methods have been applied successfully in many fields. In this paper, three machine learning algorithms, including partial least squares-discriminant analysis (PLS-DA), adaptive boosting (AdaBoost), and light gradient boosting machine (LGBM), were applied to establish models for predicting the Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET for short) properties, namely Caco-2, CYP3A4, hERG, HOB, MN of anti-breast cancer compounds. To the best of our knowledge, the LGBM algorithm was applied to classify the ADMET property of anti-breast cancer compounds for the first time. We evaluated the established models in the prediction set using accuracy, precision, recall, and F1-score. Compared with the performance of the models established using the three algorithms, the LGBM yielded most satisfactory results (accuracy > 0.87, precision > 0.72, recall > 0.73, and F1-score > 0.73). According to the obtained results, it can be inferred that LGBM can establish reliable models to predict the molecular ADMET properties and provide a useful tool for virtual screening and drug design researchers.

Medicinal chemistry aspects and synthetic strategies of coumarin as aromatase inhibitors: an overview.

Coumarin is a bicyclic oxygen bearing heterocyclic scaffold formed by fusion of benzene with the pyrone ring. Because of its unique physicochemical characteristics and the ease with which it may be transformed into a wide range of functionalized coumarins duringsynthesis, coumarin provides a privileged scaffold for medicinal chemists. As a result, many coumarin derivatives have been developed, synthesized, and evaluated to target a variety of therapeutic domains, thereby making it an attractive template for designing novel anti-breast cancer compounds. The main culprit in estrogen overproduction in the estrogen-dependent breast cancer (EDBC), is the enzyme aromatase (AR), and it is thought to be a significant target for the effective treatment of EDBC. Considering coumarins versatility, this review presents a detailed overview of diverse study of aromatase as a target for coumarins. An overview of structure-activity relationship analysis of coumarin core is also included so as to summarize the desired pharmacophoric features essential for design and development of aromatase inhibitors (AIs) using coumarin core. Identification of key synthesis techniques that could aid researchers in designing and developing novel analogues with significant anti-breast cancer properties along with their mechanism of action have also been covered in the current review.

Serial fuzzy system algorithm for predicting biological activity of anti-breast cancer compounds

Serial fuzzy system algorithm for predicting biological activity of anti-breast cancer compounds

Novel 1,3-Thiazole Analogues with Potent Activity against Breast Cancer: A Design, Synthesis, In Vitro, and In Silico Study.

Breast cancer is the most common cancer in women, responsible for over half a million deaths in 2020. Almost 75% of FDA-approved drugs are mainly nitrogen- and sulfur-containing heterocyclic compounds, implying the importance of such compounds in drug discovery. Among heterocycles, thiazole-based heterocyclic compounds have demonstrated a broad range of pharmacological activities. In the present study, a novel set of 1,3-thiazole derivatives was designed and synthesized based on the coupling of acetophenone derivatives, and phenacyl bromide was substituted as a key reaction step. The activity of synthesized compounds was screened against the proliferation of two breast cancer cell lines (MCF-7 and MDA-MB-231). Almost all compounds exhibited a considerable antiproliferative activity toward the breast cancer cells as compared to staurosporine, with no significant cytotoxicity toward the epithelial cells. Among the synthesized compounds, compound 4 exhibited the most potent antiproliferative activity, with an IC50 of 5.73 and 12.15 µM toward MCF-7 and MDA-MB-231 cells, respectively, compared to staurosporine (IC50 = 6.77 and 7.03 µM, respectively). Exploring the mechanistic insights responsible for the antiproliferative activity of compound 4 revealed that compound 4 possesses a significant inhibitory activity toward the vascular endothelial growth factor receptor-2 (VEGFR-2) with (IC50 = 0.093 µM) compared to Sorafenib (IC50 = 0.059 µM). Further, compound 4 showed the ability to induce programmed cell death by triggering apoptosis and necrosis in MCF-7 cells and to induce cell cycle arrest on MCF-7 cells at the G1 stage while decreasing the cellular population in the G2/M phase. Finally, detailed in silico molecular docking studies affirmed that this class of compounds possesses a considerable binding affinity toward VEGFR2 proteins. Overall, these results indicate that compound 4 could be a promising lead compound for developing potent anti-breast cancer compounds.

In Vitro Growth Inhibition, Caspase-Dependent Apoptosis, and S and G2/M Phase Arrest in Breast Cancer Cells Induced by Fluorine-Incorporated Gold I Compound, Ph3PAu[SC(OMe)=NC6H4F-3

Gold-based anticancer compounds have been attracting increasing research interest due to their ability to kill cancer cells resistant to platinum-based compounds. Gold I- and gold III-based complexes have shown satisfactory anticancer activities. In this study, two new fluorine-incorporated gold (I) compounds such as Ph3PAu[SC(OMe)=NC6H4F-3] and DPPFeAu2[(SC(OMe)=NC6H4F-3)]2 were evaluated for their in vitro activities against human breast cancer cell lines, primary breast cancer cells, and breast cancer stem cells (parental breast cancer stem cells, BCSC-P, and breast cancer stem cells, BCSC). Assays for growth inhibition and cytotoxicity, including real-time cell analysis, were carried out to screen effective antibreast cancer compounds. In addition, further in vitro assays such as apoptosis, caspase 3/7 activity, and cell cycle analysis were performed to observe the action and mechanism of killing breast cancer cells by the selected gold I compound, Ph3PAu[SC(OMe)=NC6H4F-3]. The gold (I) compound, Ph3PAu[SC(OMe)=NC6H4F-3], showed low toxicity to H9c2 normal cells and significant growth inhibition in MDA-MB-231 and MCF-7 cells, primary breast cancer cells, and breast cancer stem cells (BCSC-P and BCSC). The IC50 doses of the gold (I) compound Ph3PAu[SC(OMe)=NC6H4F-3] against the breast cancer cell lines MDA-MB-231 and MCF-7 were approximately 6-fold lower than that of cisplatin (cis-diamineplatinum (II) dichloride, CDDP). Moreover, the compound Ph3PAu[SC(OMe)=NC6H4F-3] induced caspase 3/7-dependent apoptosis and cell cycle arrest at S and G2/M phases. Ph3PAu[SC(OMe)=NC6H4F-3], a gold (I) compound incorporated with fluorine, is a potential candidate for the treatment of breast cancer.

Chemo-informatics activity prediction, ligand based drug design, Molecular docking and pharmacokinetics studies of some series of 4, 6-diaryl-2-pyrimidinamine derivatives as anti-cancer agents

BackgroundThe most well-known cause of cancer deaths identified in female is breast cancer. Several drugs approved by the food and drug administration (FDA) for the treatment of breast cancer may have adverse health effects. This research is aimed at developing a QSAR model and utilize it to predict the inhibitive activities of newly designed novel compounds, examine their ADMET and drug-likeness properties and carry out molecular docking studies between the designed compounds and the VEGFR-2 receptors in order to identify the essential amino acid residues involved in protein–ligand interactions and possible mechanism of action of the designed compounds.ResultsThe first model was selected as the best because of its fitness statistically with the following assessment parameters: R2train = 0.832, R2adj = 0.79, R2ext = 0.62, Q2 = 0.68, and LOF = 0.14509. Compound 11 was selected as a template to design new powerful compounds based on its low residual and high pIC50 values. Majority of the designed compounds has predicted pIC50 greater than that of the lead compound and the standard drug (Sunitinib) used as reference. Molecular docking studies results of the designed compounds revealed that they have higher docking scores than the template and the reference drug (Sunitinib) and are found to bind to the VEGFR-2 receptor in a similar manner to the reference drug. Pharmacokinetics and ADMET properties revealed that the designed compounds passed drug-likeness criteria because they did not violate more than 1 Lipinski’s rule of Five, They are uniformly distributed to the brain and are assumed to penetrate the central nervous system and finally they are all found to non-toxic and orally bioavailable.ConclusionThe developed model was therefore found to be efficient in predicting the pIC50 of Anti breast cancer compounds that are yet to be synthesized and it also help in reducing the cost and synthetic duration the compounds. The result of this research confirmed that the designed compounds may be developed as novel VEGFR-2 inhibitors.

Biochemical and histopathological evaluation of an in vivo model of breast cancer

Though, the clinical management of breast cancer has improved significantly over the past 30 years, it still remains the leading cause of cancer-related female death worldwide. Prevention is the fundamental issue in breast cancer control, for which identification markers in terms of initiation and promotion are necessary. To understand this, an animal model which can recapitulate the early symptoms of breast cancer development and progression is required. Present study is an attempt to develop a convenient and economical in-vivo animal model of breast cancer suitable to conduct such study. Female Wistar and SD rats were injected with different doses and routes of administration of 7, 12-Dihydroxymethylbenz (a) anthracene (DMBA). Animals were observed for the presence of visible/palpable tumours in mammary glands. Various parameters (Tumor morphology, oxidative stress and histopathological studies were studied in different tissues (mammary, lungs, kidney, liver) after the appearance of mammary tumours in rats. After 14 weeks all the animals developed breast carcinomas. The results of this study revealed a significant difference in oxidative stress parameters between DMBA treated and control groups and these alterations were strain dependent. The H&E staining of mice mammary tissue showed development of metaplastic triple negative breast cancer. Immunohistochemistry observation confirmed the triple negative nature of mammary tumours developed in the mice. Data confirmed that DMBA can be used as breast cancer initiator and present model can be further exploited to screen potential anti-breast cancer compounds in vivo.

Computer modeling of some anti-breast cancer compounds

The research was aimed at exploring the biological activities of novel series of β-lactam derivatives against MCF-7 breast cancer cell lines via computer modeling such as quantitative structure-activity relationship (QSAR), designing new compounds and analyzing the drug likeliness of designed compounds. The QSAR model was highly robust as it also conforms to the least minimum requirement for QSAR model from the statistical assessments with a correlation coefficient squared (R2) of 0.8706, correlation coefficient adjusted squared (R2adj) of 0.8411, and cross-validation coefficient (Q2) of 0.7844. The external validation of R2pred was calculated as 0.6083 for model 4. The model parameters (MATS5i and MATS1s) were used in designing new derivative compounds with higher potency against estrogen-positive breast cancer. The pharmacokinetics test on the restructured compounds revealed that all the compounds passed the drug likeness test and they could further proceed to clinical trials. These reveal a breakthrough in medicine, in the research for breast cancer drug with higher effectiveness against the MCF-7 cell line.

Synthesis and anticancer evaluation of N-benzoyl-N'-phenyltiourea derivatives against human breast cancer cells (T47D)

New anti-breast cancer compounds have been found and may prove to have stronger activity. To predict the activities of N-benzoyl-N'-phenylthiourea (BPTU) derivatives, namely N-(3-chloro)benzoyl-N'-phenylthiourea (3-Cl-BPTU) and N-(3,4-dichloro)benzoyl-N'-phenylthiourea (3,4-2Cl-BPTU) with Sirtuin-1 receptor (PDB code: 4I5I), molecular docking was conducted at the beginning of this study. The compounds were then synthesized from benzoyl chloride derivatives and N-phenylthiourea. Molecular structure was confirmed using FTIR, 1H NMR, 13C NMR and Mass Spectra, while the anticancer activity was tested in vitro against human breast cancer cells (T47D) using MTT assay. The results indicated that the anti-cancer activities of the test compounds were better than those of the hydroxyurea as the reference compound, evidenced by the Rerank Score (RS). Furthermore, cytotoxic effect of 3-Cl-BPTU (IC50: 0.43 mM) and 3,4-dichloro-BPTU (IC50: 0.85 mM) showed better result compared with hydroxyurea (IC50: 4.58 mM). Therefore, we concluded that these compounds could possess termendous potential as the candidate for a new anticancer drug.

In silico analysis of sea cucumber bioactive compounds as anti-breast cancer mechanism using autodock vina

In recent years, the potential of marine natural products as anticancer agents, specifically for breast cancer, has been examined. The sea cucumber (Holothuroidea: Echinodermata) is known to contain triterpene glycosides, which have shown anticancer or cytotoxic activity. In this research, molecular docking of selected sea cucumber bioactive compounds was conducted on five receptor targets that play an important role in breast cancer: estrogen receptor alpha (ER-α), fibroblast growth factor receptor 1 (FGFR1), vascular endothelial growth factor receptor 2 (VEGFR2), progesterone receptor (PR), and insulin-like growth factor 1 receptor (IGFR1). The purpose of this was to observe the interaction between active compounds and the active site of breast cancer receptor targets. Holothurin A gave the lowest binding energy (-7.1 kcal/mol) and was involved in a hydrogen bond with amino acid His-516 when superposition towards to E4D cocrystal was present. Holothurin A also had a similar posing with raloxifene, in which the hydrogen bond with His-516 with a RMSD value of 3.3 A was observed with superposition towards to the positive control raloxifene. The analysis and visualization results of 24-dehidroechinoside that was superposed on E4D cocrystal, BMI cocrystal, and positive control raloxifene showed that 24-dehidroechinoside had a hydrophobic interaction with amino-acid residue Leu-346, a strong hydrogen bond to Gln-977, as well as a hydrogen bond to Thr-347 in a distance of 3.7 A, and a hydrophobic interaction with amino-acid residue Ala-350. The most potent in silico anti-breast cancer compounds in sea cucumbers are holothurin A and 24-dehidroechinoside. Holothurin A is active as an anti-breast cancer agent by inhibiting ER-α, while 24-dehidroechinoside inhibits both ER-α and IGFR1.

Screening active anti-breast cancer compounds from cortex magnolia officinalis by MCF-7 cell membrane chromatography coupled with UHPLC-ESI-MS/MS

MCF-7/CMC-HPLC-MS/MS for screening active anti-breast cancer compounds from Traditional Chinese Medicines.

Spiro[pyrrolidine-3, 3´-oxindole] as potent anti-breast cancer compounds: Their design, synthesis, biological evaluation and cellular target identification.

The spiro[pyrrolidine-3, 3´-oxindole] moiety is present as a core in number of alkaloids with substantial biological activities. Here in we report design and synthesis of a library of compounds bearing spiro[pyrrolidine-3, 3´-oxindole] motifs that demonstrated exceptional inhibitory activity against the proliferation of MCF-7 breast cancer cells. The synthesis involved a one pot Pictet Spengler-Oxidative ring contraction of tryptamine to the desired scaffolds and occurred in 1:1 THF and water with catalytic trifluoroacetic acid and stoichiometric N-bromosuccinimide as an oxidant. Phenotypic profiling indicated that these molecules induce apoptotic cell death in MCF-7 cells. Target deconvolution with most potent compound 5l from the library, using chemical proteomics indicated histone deacetylase 2 (HDAC2) and prohibitin 2 as the potential cellular binding partners. Molecular docking of 5l with HDAC2 provided insights pertinent to putative binding interactions.

Effects of Ethyl Acetate Extracts from the Polycephalomyces nipponicus Isolate Cod-MK1201 (Ascomycetes) against Human Pathogenic Bacteria and a Breast Cancer Cell Line.

This study aimed to identify a suitable organic solvent for extracting bioactive compounds from Polycephalomyces nipponicus and to evaluate the antibacterial and anticancer activities of the extracts obtained. Only extracts obtained with ethyl acetate exhibited antibacterial activity, so ethyl acetate was chosen for large-scale extraction. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against Gram-positive and Gram-negative human pathogenic bacteria of the 3 ethyl acetate-derived extracts-ethyl acetate extract from P. nipponicus (PN-ME), ethyl acetate extract after defatting (PN-ME*), and ethyl acetate extract after refluxation (PN-ME')-were determined. PN-ME' exhibited the most potent activity, inhibiting 12 of the 18 test bacteria, especially Bacillus cereus ATCC 11778 and Vibrio cholera (O1) DMST 9700, with low MIC and MBC values. PN-ME* showed greater inhibitory activity than PN-ME. The effects of the extracts on bacterial cell morphology were also determined. After 120 minutes of treatment with PN-ME* or PN-ME', B. cereus ATCC 11778 exhibited an abnormal rod-shaped cell structure, with some cells elongated to multiple times their original size and others appearing collapsed. V cholera (O1) DMST 9700 cells showed shrinkage and the formed subsurface cavities. PN-ME* and PN-ME' also inhibited the growth of MCF-7 breast cancer cells. In conclusion, the fungal isolate P. nipponicus Cod-MK1201 represents a source of antibacterial and anti-breast cancer compounds.

Model for Classification of ChEMBL Dataset of Anti-breast cancer Compounds According to Multiple Pharmacological Parameters, Biological Assays, and Receptors

Model for Classification of ChEMBL Dataset of Anti-breast cancer Compounds According to Multiple Pharmacological Parameters, Biological Assays, and Receptors

Magnolol‐induced inhibition of tumor growth in systemic malignancies

The commentary illustrates the significant tumor attenuating effects of magnolol and refers to the article on "Screening active anti-breast cancer compounds from Cortex Magnolia officinalis by 2D LC-MS" (X. Hou, et al., J. Sep. Sci. 2013, 36 (4), 706-712). On the basis of the literature, there is definitively need for further studies to fully understand the magnolol reation pathways and to harness the antineoplastic effects.