Novel Hybrid Compounds Containing Benzofuroxan and Aminothiazole Scaffolds: Synthesis and Evaluation of Their Anticancer Activity

A series of novel hybrid compounds containing benzofuroxan and 2-aminothiazole moieties are synthesized via aromatic nucleophilic substitution reaction. Possible reaction pathways have been considered quantum-chemically, which allowed us to suggest the most probable products. The quantum chemical results have been proved by X-ray data on one compound belonging to the synthesized series. It was shown that the introduction of substituents to both the thiazole and amine moieties of the compounds under study strongly influences their UV/Vis spectra. Initial substances and obtained hybrid compounds have been tested in vitro as anticancer agents. Target compounds showed selectivity towards M-HeLa tumor cell lines and were found to be more active than starting benzofuroxan and aminothiazoles. Furthermore, they are considerably less toxic to normal liver cells compared to Тamoxifen. The mechanism of action of the studied compounds can be associated with the induction of apoptosis, which proceeds along the mitochondrial pathway. Thus, new hybrids of benzofuroxan are promising candidates for further development as anticancer agents.

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Triptolide induces caspase-dependent cell death mediated via the mitochondrial pathway in leukemic cells

Blood ◽

10.1182/blood-2005-09-3898 ◽

2006 ◽

Vol 108 (2) ◽

pp. 630-637 ◽

Cited By ~ 120

Author(s):

Bing Z. Carter ◽

Duncan H. Mak ◽

Wendy D. Schober ◽

Teresa McQueen ◽

David Harris ◽

...

Keyword(s):

Cell Death ◽

Anticancer Agents ◽

Chinese Herb ◽

Mitochondrial Pathway ◽

Leukemic Cells ◽

Cytochrome C Release ◽

Knock Out ◽

Dependent Cell ◽

Induced Apoptosis

Triptolide, a diterpenoid isolated from the Chinese herb Tripterygium wilfordii Hook.f, has shown antitumor activities in a broad range of solid tumors. Here, we examined its effects on leukemic cells and found that, at 100 nM or less, it potently induced apoptosis in various leukemic cell lines and primary acute myeloid leukemia (AML) blasts. We then attempted to identify its mechanisms of action. Triptolide induced caspase-dependent cell death accompanied by a significant decrease in XIAP levels. Forced XIAP overexpression attenuated triptolide-induced cell death. Triptolide also decreased Mcl-1 but not Bcl-2 and Bcl-XL levels. Bcl-2 overexpression suppressed triptolide-induced apoptosis. Further, triptolide induced loss of the mitochondrial membrane potential and cytochrome C release. Caspase-9 knock-out cells were resistant, while caspase-8–deficient cells were sensitive to triptolide, suggesting criticality of the mitochondrial but not the death receptor pathway for triptolide-induced apoptosis. Triptolide also enhanced cell death induced by other anticancer agents. Collectively, our results demonstrate that triptolide decreases XIAP and potently induces caspase-dependent apoptosis in leukemic cells mediated through the mitochondrial pathway at low nanomolar concentrations. The potent antileukemic activity of triptolide in vitro warrants further investigation of this compound for the treatment of leukemias and other malignancies.

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Synthesis, Molecular Docking and Anticancer Activity of Novel 1,3-Thiazolidin-4-Ones

Pharmaceutical Sciences ◽

10.34172/ps.2020.95 ◽

2020 ◽

Vol 27 (3) ◽

pp. 345-352

Author(s):

Ramesh Sawant ◽

Jyoti Wadekar ◽

Rushikesh Ukirde ◽

Ganesh Barkade

Keyword(s):

Anticancer Activity ◽

Anticancer Agents ◽

Cancer Cell Line ◽

Lead Compounds ◽

Growth Inhibitory ◽

Growth Inhibitory Activity ◽

Further Development ◽

Mcf 7 ◽

Clinical Strategy

Background: Cancer is a major cause of death all over the globe. Controlling cell division byinhibition of mitosis is the most successful clinical strategy for cancer treatment. The developmentof novel anticancer agents is the most important area in medicinal chemistry and drug discoveryresearch. Thiazolidine is the multifunctional nucleus which shows a number of pharmacologicalactivities like anticancer, anti-inflammatory, antioxidant, antibacterial, antifungal, antidiabetic,antihyperlipidemic and antiarthritic. Methods: In a present study series of 2-substituted-3-(1H-benzimidazole-2-yl)-thiazolidin-4-ones were designed, synthesized by the microwave-assisted system, and characterized bymelting point, IR, 1H NMR, and mass spectroscopy. All the newly synthesized compoundswere examined for their in vitro anticancer activity against breast cancer cell line MCF-7 bySulforhodamine B (SRB) assay. Results: The compounds AB-12 (GI50: 28.5 μg/ml) and AB-6 (GI50: 50.7 μg/ml) exhibitedsignificant cell growth inhibitory activity. Conclusion: These results indicate that compound AB-12 and AB-6 as related polo-like kinase1inhibitors compounds could be lead compounds for further development of anticanceragents.

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Design of Oleanolic Acid-Based Hybrid Compounds as Potential Pharmaceutical Scaffolds

Letters in Drug Design & Discovery ◽

10.2174/1570180818666210604112451 ◽

2021 ◽

Vol 18 ◽

Author(s):

Vuyolwethu Khwaza ◽

Opeoluwa Oyehan Oyedeji ◽

Blessing Atim Aderibigbe ◽

Eric Morifi ◽

Youmbi Thierry Fonkui ◽

...

Keyword(s):

Oleanolic Acid ◽

Klebsiella Oxytoca ◽

In Vitro Cytotoxicity ◽

Hybrid Compounds ◽

Sulforhodamine B ◽

Cytotoxicity Studies ◽

Sulforhodamine B Assay ◽

Ic50 Values ◽

Further Development

Background: Infectious diseases as well as cancer are the leading causes of death worldwide. Drug resistance usually results in their treatment requiring a combination of two or more drugs. Objective: Oleanolic-based hybrid compounds were prepared via esterification and characterized using FTIR, NMR, and LC-MS. In vitro antibacterial and in vitro cytotoxicity studies were performed. Method: Oleanolic acid was hybridized with selected known pharmaceutical scaffolds via the carboxylic acid functionality to develop therapeutics with increased biological activity. Antibacterial activity was determined using the micro-dilution assay against selected Gram-positive and Gram-negative bacteria and cytotoxicity using the sulforhodamine B assay. Results: Compound 8 displayed potent antibacterial effect against five strains of bacteria such as Bacillus subtilis, Staphylococcus aureus, Proteus vulgaris, Klebsiella oxytoca, and Escherichia coli with MIC values of 1.25, 0.078, 0.078, 1.25, 1.25 mg/mL when compared to the control, oleanolic acid (MIC = 2.5 mg/mL). Furthermore, in vitro cytotoxicity, as determined using the SRB assay, against selected cancer cells revealed that compound 7 was the most cytotoxic to MDA, DU145, and MCF-7 cell lines with IC50 values of 69.87±1.04, 73.2±1.08, and 85.27±1.02 µg/mL, respectively, than oleanolic acid with an IC50 ˃200 µg/mL. Conclusion: Hybridization of oleanolic acids was successful, and further development of these potential antibacterial compounds with reduced cytotoxicity is warranted.

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Design of Novel 4-Aminobenzofuroxans and Evaluation of Their Antimicrobial and Anticancer Activity

International Journal of Molecular Sciences ◽

10.3390/ijms21218292 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8292

Author(s):

Elena Chugunova ◽

Almir Gazizov ◽

Marina Sazykina ◽

Nurgali Akylbekov ◽

Anastasiya Gildebrant ◽

...

Keyword(s):

Activation Barrier ◽

Normal Liver ◽

Bacterial Biofilm ◽

Biofilm Growth ◽

Factors Affecting ◽

Fungistatic Activity ◽

Quantum Chemistry Calculations ◽

Anti Cancer ◽

Aromatic Nucleophilic Substitution Reaction

A series of novel 4-aminobenzofuroxan derivatives containing aromatic/aliphatic amines fragments was achieved via aromatic nucleophilic substitution reaction of 4,6-dichloro-5-nitrobenzofuroxan. The quantum chemistry calculations were performed to identify the factors affecting the regioselectivity of the reaction. The formation of 4-substituted isomer is favored both by its greater stability and the lower activation barrier. Antimicrobial activity of the obtained compounds has been evaluated and some of them were found to suppress effectively bacterial biofilm growth. Fungistatic activity of 4-aminobenzofuroxans were tested on two genetically distinct isolates of M. nivale. The effect of some benzofuroxan derivatives is likely to be more universal against different varieties of M. nivale compared with benzimidazole and carbendazim. Additionally, their anti-cancer activity in vitro has been tested. 4-aminofuroxans possessing aniline moiety showed a high selectivity towards MCF-7 and M-HeLa tumor cell lines. Moreover, they exhibit a significantly lower toxicity towards normal liver cells compared to Doxorubicin and Tamoxifen. Thus, benzofuroxans containing aromatic amines fragments in their structure are promising candidates for further development both as anti-cancer and anti-microbial agents.

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Involvement of Reactive Oxygen Species in the Hepatorenal Toxicity of Actinomycin V In Vitro and In Vivo

Marine Drugs ◽

10.3390/md18080428 ◽

2020 ◽

Vol 18 (8) ◽

pp. 428

Author(s):

Fu-juan Jia ◽

Zhuo Han ◽

Jia-hui Ma ◽

Shi-qing Jiang ◽

Xing-ming Zhao ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Therapeutic Agent ◽

Reactive Oxygen ◽

Normal Liver ◽

Oxygen Species ◽

First Line ◽

Liver And Kidney ◽

Further Development

The high toxicity of actinomycin D (Act D) severely limits its use as a first-line chemotherapeutic agent in the clinic. Actinomycin V (Act V), an analog of Act D, exhibited strong anticancer activity in our previous studies. Here, we provide evidence that Act V has less hepatorenal toxicity than Act D in vitro and in vivo, associated with the reactive oxygen species (ROS) pathway. Compared to Act D, Act V exhibited considerably stronger sensitivity for cancer cells and less toxicity to human normal liver LO-2 and human embryonic kidney 293T cells using the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assay. Notably, Act V caused less damage to both the liver and kidney than Act D in vivo, indicated by organ to body weight ratios, as well as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and serum creatinine (Scr) levels. Further experiments showed that the ROS pathway is involved in Act V-induced hepatorenal toxicity. Act V generates ROS and accumulates malondialdehyde (MDA), reducing levels of superoxide dismutase (SOD) and glutathione (GSH) in LO-2 and 293T cells. These findings indicate that Act V induces less hepatorenal toxicity than Act D in vitro and in vivo and merits further development as a potential therapeutic agent for the treatment of cancer.

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Empirical Modeling of Zn/ZnO Nanoparticles Decorated/Conjugated with Fotolon (Chlorine e6) Based Photodynamic Therapy towards Liver Cancer Treatment

Micromachines ◽

10.3390/mi10010060 ◽

2019 ◽

Vol 10 (1) ◽

pp. 60 ◽

Cited By ~ 8

Author(s):

Seemab Iqbal ◽

Muhammad Fakhar-e-Alam ◽

M. Atif ◽

Nasar Ahmed ◽

Aqrab -ul-Ahmad ◽

...

Keyword(s):

Photodynamic Therapy ◽

Cancer Treatment ◽

Zno Nanoparticles ◽

Normal Liver ◽

Empirical Modeling ◽

In Vivo Model ◽

P Value ◽

X Ray ◽

Chlorine E6

The current study is based on Zn/ZnO nanoparticles photodynamic therapy (PDT) mediated effects on healthy liver cells and cancerous cells. The synthesis of Zn/ZnO nanoparticles was accomplished using chemical and hydrothermal methods. The characterization of the synthesized nanoparticles was carried out using manifold techniques (e.g., transmission electron microscopy (TEM), X-ray diffraction (XRD), and energy dispersive X-ray spectroscopy (EDS)). In order to study the biotoxicity of the grown nanoparticles, they were applied individually and in conjunction with the third generation photosensitiser Fotolon (Chlorine e6) in the in vivo model of the normal liver of the Wister rat, and in the in vitro cancerous liver (HepG2) model both in the dark and under a variety of laser exposures (630 nm, Ultraviolet (UV) light). The localization of ZnO nanoparticles was observed by applying fluorescence spectroscopy on a 1 cm2 selected area of normal liver, whereas the in vitro cytotoxicity and reactive oxygen species (ROS) detection were carried out by calculating the loss in the cell viability of the hepatocellular model by applying a neutral red assay (NRA). Furthermore, a statistical analysis is carried out and it is ensured that the p value is less than 0.05. Thus, the current study has highlighted the potential for applying Zn/ZnO nanoparticles in photodynamic therapy that would lead to wider medical applications to improve the efficiency of cancer treatment and its biological aspect study.

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EVALUATION OF IN VITRO CYTOTOXIC AND ANTICANCER ACTIVITY OF HEPATOPROTECTIVE POLYHERBAL FORMULATION IN CELL LINE MODEL

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2019.v12i4.32118 ◽

2019 ◽

pp. 320-325

Author(s):

JAYACHANDRA KUNCHA ◽

THIRUGNANASAMBANTHAM P ◽

KUMARAN S ◽

NARAYANAN N ◽

SHARMILA DEVI V

Keyword(s):

Anticancer Activity ◽

Cell Lines ◽

Cancer Cell ◽

Anticancer Agents ◽

Kidney Cell ◽

Normal Liver ◽

Cancer Cell Lines ◽

Polyherbal Formulation ◽

Ic50 Values

Introduction: The use of natural products as anticancer agents has a long history that began with folklore medicine and through the years has been incorporated into traditional and allopathic medicine. Several drugs currently used are derived from medicinal plants. Objective: The main objective of this study is to investigate the cytotoxic potential of hepatoprotective polyherbal formulation in normal and cancer cell lines. Methods: A 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyltetrazolium bromide assay was utilized to screen the cytotoxic activity. Results: The results revealed that the formulation does not induce much mortality in normal liver and kidney cell lines, and LC50 value of liver cell lines was found 1716.355 μg/ml and kidney cell lines 2464.910 μg/ml. The in vitro anticancer activity was performed on liver, colon, and prostate cancer cell lines, and IC50 values are found 2.077, 3.850, and 11.989 μg/ml, respectively, which show excellent anticancer activity. Conclusion: Based on the results obtained, the hepatoprotective polyherbal formulation is safe for normal cells and cytotoxic for cancer cells. Further, identification and quantification of phytoconstituents responsible for the activity are in progress.

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Fragment-based Discovery of Potential Anticancer Lead: Computational and in Vitro Studies

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200620195025 ◽

2020 ◽

Vol 16 ◽

Author(s):

Abdulmalek A. Balgoname ◽

Sufyan M. Alomair ◽

Abdulrahman K. AlMubireek ◽

Mohammed A. Khedr

Keyword(s):

Cell Lines ◽

Anticancer Agents ◽

Prostatic Cancer ◽

Growth Factor Receptor ◽

Pharmacophore Model ◽

In Silico Study ◽

Epidermal Growth ◽

Cancer Tissues ◽

Further Development

Background: The human epidermal growth factor receptor 2 (HER2) plays a role in the propagation of different types of cancers. It was identified in many types of cancer tissues like; breast, ovarian, lung, prostate, and stomach cancers. Therefore, inhibition of HER2 can lead to the discovery of novel anticancer agents. Objective: The study aims to discover a lead scaffold with drug-like properties and high affinity toward HER2 Methods: A list of HER2 inhibitors were collected, analyzed, and subjected to fragmentation and molecular docking. The in silico study computed the affinity, clash score, and ligand entropy score. A pharmacophore model for an ideal inhibitor designed, and tested against breast, lung, and prostatic cancer cell lines. Results: The discovered lead compound achieved several hydrogen bonds with the primary residues found in the active site of HER2, such as; Met801, Gln99, Lys753, and Thr862 with a computational affinity – 13.45 kcal/mol. In addition to a hydrophobic interaction with leu800. The in vitro cytotoxic activity against; breast cancer MCF-7, prostatic cancer PC-3 and lung cancer A-549 cell lines showed (IC50 = 86.38 ±1.1 mmol/ml), (IC50 = 157.02 ±1.3 mmol/ml), and (IC50 = 181.1 ±2.4 mmol/ml) respectively. Conclusion: The discovered lead is an excellent drug-like candidate for further development and optimization.

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Natural Trienoic Acids as Anticancer Agents: First Stereoselective Synthesis, Cell Cycle Analysis, Induction of Apoptosis, Cell Signaling and Mitochondrial Targeting Studies

Cancers ◽

10.3390/cancers13081808 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1808

Author(s):

Vladimir A. D’yakonov ◽

Alexey A. Makarov ◽

Lilya U. Dzhemileva ◽

Ilfir R. Ramazanov ◽

Elina Kh. Makarova ◽

...

Keyword(s):

Anticancer Agents ◽

Tyrosine Kinases ◽

Intracellular Signaling ◽

Topoisomerase I ◽

Stereoselective Synthesis ◽

Mitochondrial Pathway ◽

Cytotoxic Activities ◽

Human Embryonic Kidney Cells ◽

In Silico Studies

The first Z-stereoselective method was developed for the synthesis of unsaturated acids containing a 1Z,5Z,9Z-triene moiety in 61–64% yields using the new Ti-catalyzed cross-coupling of oxygen-containing and aliphatic 1,2-dienes as the key synthetic step. It was shown for the first time that trienoic acids with non-methylene-interrupted Z-double bonds show moderate cytotoxic activities against tumor cell lines (Jurkat, K562, U937, HL60, HeLa), human embryonic kidney cells (Hek293), normal fibroblasts and human topoisomerase I (hTop1) inhibitory activity in vitro. The synthesized acids efficiently initiate apoptosis of Jurkat tumor cells, with the cell death mechanism being activated by the mitochondrial pathway. A probable mechanism of topoisomerase I inhibition was also hypothesized on the basis of in silico studies resorting to docking. The activation and inhibition of the most versatile intracellular signaling pathways (CREB, JNK, NFkB, p38, ERK1/2, Akt, p70S6K, STAT3 and STAT5 tyrosine kinases) responsible for cell proliferation and for initiation of apoptosis were studied by multiplex assay technology (Luminex xMAP).

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In Vitro Antitumor Evaluation of Acrylic Acid Derivatives Bearing Quinolinone Moiety as Novel Anticancer Agents

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666211103105255 ◽

2021 ◽

Vol 21 ◽

Author(s):

Islam Zaki ◽

Sarah A. Eid ◽

Mohamed S. Elghareb ◽

Al-Shimaa M. Abas ◽

Fatten Z. Mohammed ◽

...

Keyword(s):

Acrylic Acid ◽

Cell Lines ◽

Cancer Cell ◽

Anticancer Agents ◽

Cancer Cell Lines ◽

Cytotoxic Agents ◽

Hct 116 ◽

Emergence Of Resistance ◽

Further Development

Background: Due to the emergence of resistance to available anticancer agents, the demand for new cytotoxic agents has grown. Objective: This study aims at synthesis and cytotoxic evaluation of new acrylic acid derivatives bearing quinolinone and halogenated quinolinone derivatives against three cancer cell lines. Methods: New acrylic acid derivatives bearing quinolinone and halogenated quinolinone moieties were synthesized and screened for their cytotoxic activity against breast MCF-7, liver HepG2, and colon HCT-116 cancer cell lines. Conclusion: Acrylic acid derivatives bearing quinolinone and halogenated quinolinone moieties represent an important core and could be used as a lead for further development of drug compounds in order to achieve promising therapeutic results.

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