Design, Synthesis and Docking Studies of Novel Macrocyclic Pentapeptides as Anticancer Multi-Targeted Kinase Inhibitors

A series of macrocyclic pyrido-pentapeptide candidates 2–6 were synthesized by using N,N-bis-[1-carboxy-2-(benzyl)]-2,6-(diaminocarbonyl)pyridine 1a,b as starting material. Structures of the newly synthesized compounds were established by IR, 1H and 13C-NMR, and MS spectral data and elemental analysis. The in-vitro cytotoxicity activity was investigated for all compounds against MCF-7 and HepG-2 cell lines and the majority of the compounds showed potent anticancer activity against the tested cell lines in comparison with the reference drugs. Out of the macrocyclic pyrido-pentapeptide based compounds, 5c showed encouraging inhibitory activity on MCF-7 and HepG-2 cell lines with IC50 values 9.41 ± 1.25 and 7.53 ± 1.33 μM, respectively. Interestingly, 5c also demonstrated multitarget profile and excellent inhibitory activity towards VEGFR-2, CDK-2 and PDGFRβ kinases. Furthermore, molecular modeling studies of the compound 5c revealed its possible binding modes into the active sites of those kinases.

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In vitro Cytotoxicity Activity of Chrysin, Morin and Resveratrol Against MCF-7 Breast Cancer Cell Lines

Biosciences Biotechnology Research Asia ◽

10.13005/bbra/2310 ◽

2016 ◽

Vol 13 (3) ◽

pp. 1633-1637 ◽

Cited By ~ 1

Author(s):

Arlene Thomas ◽

Niraja Ranadive ◽

Harisha Nayak ◽

Sneha Surendran ◽

Madhavan Nampoothiri ◽

...

Keyword(s):

Breast Cancer ◽

Cell Lines ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cancer Cell Lines ◽

In Vitro Cytotoxicity ◽

Breast Cancer Cell Lines ◽

Cytotoxicity Activity ◽

Mcf 7

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Antiproliferative Activity and Molecular Docking of Novel Double-Modified Colchicine Derivatives

Cells ◽

10.3390/cells7110192 ◽

2018 ◽

Vol 7 (11) ◽

pp. 192 ◽

Cited By ~ 9

Author(s):

Urszula Majcher ◽

Greta Klejborowska ◽

Mahshad Moshari ◽

Ewa Maj ◽

Joanna Wietrzyk ◽

...

Keyword(s):

Cell Lines ◽

Anticancer Agents ◽

Human Tumor ◽

In Vitro Cytotoxicity ◽

Binding Modes ◽

Long Term Treatment ◽

Colchicine Derivatives ◽

Β Tubulin ◽

Mcf 7

Microtubules are tubulin polymer structures, which are indispensable for cell growth and division. Its constituent protein β-tubulin has been a common drug target for various diseases including cancer. Colchicine has been used to treat gout, but it has also been an investigational anticancer agent with a known antimitotic effect on cells. However, the use of colchicine as well as many of its derivatives in long-term treatment is hampered by their high toxicity. To create more potent anticancer agents, three novel double-modified colchicine derivatives have been obtained by structural modifications in C-4 and C-10 positions. The binding affinities of these derivatives of colchicine with respect to eight different isotypes of human β-tubulin have been calculated using docking methods. In vitro cytotoxicity has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo and LoVo/DX). Computer simulations predicted the binding modes of these compounds and hence the key residues involved in the interactions between tubulin and the colchicine derivatives. Two of the obtained derivatives, 4-bromothiocolchicine and 4-iodothiocolchicine, were shown to be active against three of the investigated cancer cell lines (A549, MCF-7, LoVo) with potency at nanomolar concentrations and a higher relative affinity to tumor cells over normal cells.

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New Ferrocene Compounds as Selective Cyclooxygenase (COX-2) Inhibitors: Design, Synthesis, Cytotoxicity and Enzyme-inhibitory Activity

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520617666171003145533 ◽

2018 ◽

Vol 18 (2) ◽

pp. 295-301 ◽

Cited By ~ 8

Author(s):

Shabnam Farzaneh ◽

Elnaz Zeinalzadeh ◽

Bahram Daraei ◽

Soraya Shahhosseini ◽

Afshin Zarghi

Keyword(s):

Cell Lines ◽

Inhibitory Activity ◽

Fibroblast Cell ◽

Breast Cancer Cell Lines ◽

Ferrocene Derivatives ◽

Cox 2 ◽

Cytotoxicity Effects ◽

Cox 2 Inhibitors ◽

Mcf 7

Background: Due to the astonishing properties of ferrocene and its derivatives, it has a broad application in diverse areas. Numerous ferrocene derivatives demonstrated anti-proliferative activity. Also COX-2, as a key isoenzyme for production of prostaglandins, is frequently overexpressed in various cancers. It is now recognized that COX-2 over expression promotes tumorigenic functions which can be suppressed by COX-2 inhibitors, a phenomenon useful for the preventing of tumor progression. The combination of COX-2 inhibitors with other anti-cancer or cancer prevention drugs may reduce their side effects in future cancer prevention and treatment. Objective: Owing to high anticancer potential of ferrocene derivatives and considerable COX-2 inhibitory and cytotoxicity effects of our previously synthesized chalcones, we decided to incorporate the ferrocenyl moiety into appropriate COX-2 inhibitor chalcone based scaffold, to evaluate COX-2 inhibitory activity as well as anticancer activities. Methods: Chalcones were synthesized via clasien-schmidt condensation of methylsulfonyl aldehyde and acetyl ferrocene. Further different amines with solvent free and ultra sound condition were reacted with chalcones to have different 1-ferrocenyl-3-amino carbonyl compounds. Docking study was carried out with Auto Dock vina software. All the newly-synthesized compounds were evaluated for their cyclooxygenase-2 (COX-2) inhibitory activity using chemiluminescent enzyme assays as well as cytotoxicity activity against MCF-7 and T47D and fibroblast cell lines by MTT assay. Results: In vitro COX-1/COX-2 inhibition studies demonstrated that all compounds were selective inhibitors of the COX-2 isozyme with IC50 values in the highly potent 0.05-0.12 µM range, and COX-2 selectivity indexes (SI) in the 148.3-313.7 range. These results indicated that either potency or selectivity of COX-2 inhibitory activity was affected by the nature and size of the substituents on C-3 of propane-1-one. Also anti-proliferative and toxicity activities of synthesized compounds against breast cancer cell lines MCF-7 and T47D and fibroblast cell lines showed that the synthesized compounds had mild to moderate cytotoxicity against MCT7 and T47D breast cancer cell lines at 10 µM concentration. In vitro COX-1/COX-2 inhibition studies and anticancer activity against MCF-7, identified 1-ferrocenyl-3-(4-methylsulfonylphenyl) propen-1-one as a potent compound (IC50 COX-2 = 0.05 µM, MCF-7: % inhibition (at concentration of 10 µM) = 32.7%), and also 1-ferrocenyl-3- (propan-1-amine)-3-(4-methylsulfonylphenyl) propan-1-one showed the most selectivity on COX-2 inhibition (selectivity index= 313.7). Conclusion: A novel group of ferrocene compounds, possessing a methyl sulfonyl COX-2 pharmacophore were synthesized to investigate the effect of different substituents on selectivity and potency of COX-2 inhibitory activity and their cytotoxicity effects. This study indicates that 1-ferrocenyl-3-amino carbonyl compounds having ferrocene motif and methyl sulfonyl COX-2 pharmacophore is a suitable scaffold to design COX-2 inhibitors and anti-cancer agents.

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Design, Synthesis and Biological Evaluation of Novel Urea and Thiourea Bearing thieno[3,2-d]-pyrimidines as PI3 Kinase Inhibitors

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520618666180209151018 ◽

2018 ◽

Vol 18 (6) ◽

pp. 891-902 ◽

Cited By ~ 6

Author(s):

Srinu Bodige ◽

Parameshwar Ravula ◽

Kali Charan Gulipalli ◽

Srinivas Endoori ◽

J.N. Narendra Sharath Chandra ◽

...

Keyword(s):

Anticancer Activity ◽

Cell Lines ◽

Inhibitory Activity ◽

Intracellular Signaling ◽

Research Work ◽

Docking Studies ◽

Biological Evaluation ◽

Intracellular Enzyme ◽

Ht 29 ◽

Mcf 7

Background: Phosphatidylinositol-3-kinase α (PI3Kα) is a ubiquitous intracellular enzyme, mainly involved in intracellular signaling pathways, promotes cellular growth, proliferation, and differentiation. Therefore, inhibition of PI3K can be a hotspot in molecular targeted therapy for the treatment of cancer. Methods: The present research work involves molecular docking studies performed to screen derivatives of urea and thiourea bearing thieno [3,2-d]-pyrimidines against the active site of PI3K enzyme using MOE.2008.10. The designed structures (6a-f) and (7a-j) were synthesized by the facile synthetic methods and evaluated for their anticancer activity against HT-29 and MCF-7 cell lines and inhibitory activity against PI3Kα enzyme. Results: Among the tested compounds, 4-(4-(2-(3-(pyrimidin-2-yl)thioureido)ethyl)piperazin-1-yl)thieno[3,2- d]pyrimidine-6-carboxamide (7f) showed the highest anticancer activity against HT-29 and MCF-7 cell lines with IC50 values of 2.18 µM and 4.25 µM, respectively. Further, the same compound also exhibited potent PI3Kα inhibitory activity with IC50 value of 1.26 µM. Conclusion: Docking studies supported the initial pharmacophoric hypothesis and suggested a mode of interaction at the active binding site of PI3Kα, demonstrating that the target compounds were potential inhibitory agents for cancer therapy.

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Synthesis and In Vitro Antitumor Activity of Novel Bivalent β-Carboline-3-carboxylic Acid Derivatives with DNA as a Potential Target

International Journal of Molecular Sciences ◽

10.3390/ijms19103179 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3179 ◽

Cited By ~ 4

Author(s):

Hongling Gu ◽

Na Li ◽

Jiangkun Dai ◽

Yaxi Xi ◽

Shijun Wang ◽

...

Keyword(s):

Antitumor Activity ◽

Cell Apoptosis ◽

Docking Studies ◽

In Vitro Cytotoxicity ◽

Dependent Manner ◽

Cycle Arrest ◽

Dna Binding Affinity ◽

Dose Dependent ◽

Mcf 7

A series of novel bivalent β-carboline derivatives were designed and synthesized, and in vitro cytotoxicity, cell apoptosis, and DNA-binding affinity were evaluated. The cytotoxic results demonstrated that most bivalent β-carboline derivatives exhibited stronger cytotoxicity than the corresponding monomer against the five selected tumor cell lines (A549, SGC-7901, Hela, SMMC-7721, and MCF-7), indicating that the dimerization at the C3 position could enhance the antitumor activity of β-carbolines. Among the derivatives tested, 4B, 6i, 4D, and 6u displayed considerable cytotoxicity against A549 cell line. Furthermore, 4B, 6i, 4D, and 6u induced cell apoptosis in a dose-dependent manner, and caused cell cycle arrest at the S and G2/M phases. Moreover, the levels of cytochrome C in mitochondria, and the expressions of bcl-2 protein, decreased after treatment with β-carbolines, which indicated that 6i and 6u could induce mitochondria-mediated apoptosis. In addition, the results of UV-visible spectral, thermal denaturation, and molecular docking studies revealed that 4B, 6i, 4D, and 6u could bind to DNA mainly by intercalation.

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Molecular Docking and In Vitro Anticancer Screening of Synthesized Arylthiazole linked 2H-indol-2-one Derivatives as VEGFR-2 Kinase Inhibitors

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520621666211118102139 ◽

2021 ◽

Vol 21 ◽

Author(s):

Nishtha Shalmali ◽

Sandhya Bawa ◽

Md Rahmat Ali ◽

Sourav Kalra ◽

Raj Kumar ◽

...

Keyword(s):

Flow Cytometry ◽

Anticancer Activity ◽

Cell Lines ◽

Cancer Cell ◽

Active Sites ◽

Colorectal Adenocarcinoma ◽

Kinase Inhibitors ◽

Adenocarcinoma Cells ◽

Ic50 Values

Background: Indoline-2,3-dione comprises a leading course group of heterocycles endowed with appealing biological actions, including anticancer activity. There are significant justifications for exploring the anticancer activity of Schiff base derivatives of isatin as a vast number of reports have documented remarkable antiproliferative action of isatin nucleus against various cancer cell lines. Aims and Objectives: A series of arylthiazole linked 2H-indol-2-one derivatives (5a-t) was designed and synthesized as potential VEGFR-2 kinase inhibitors keeping the essential pharmacophoric features of standard drugs, like sunitinib, sorafenib, nintedanib, etc. They were evaluated for their in vitro anticancer activity. The aim of this study was to investigate and assess the anticancer potential of isatin-containing compounds along with their kinase inhibition activity. Methods: The title compounds were synthesized by reacting substituted isatins with para-substituted arylthiazoles using appropriate reaction conditions. Selected synthesized derivatives went under preliminary screening against a panel of 60 cancer cell lines at NCI, the USA, for single-dose and five dose assays. Molecular docking was performed to explore the binding and interactions with the active sites of the VEGFR-2 receptor (PDB Id: 3VHE). Derivatives 5a, 5b, 5c, 5d, 5g, 5h, and 5m were assessed for in vitro inhibition potency against Human VEGFR-2 using ELISA (Enzyme-Linked Immunosorbent Assay) kit. All the target compounds were determined against human colon cancer cell line SW480 (colorectal adenocarcinoma cells). Cellular apoptosis/necrosis was determined by flow cytometry using annexin V-FITC. DNA content of the cells was analyzed by flow cytometry and the cycle distribution was quantified. Results: Compounds 5a and 5g exhibited noteworthy inhibition during a five-dose assay against a panel of 60 cell lines with MID GI50 values of 1.69 and 1.54 µM, respectively. Also, both the lead compounds 5a and 5g demonstrated promising VEGFR-2 inhibitory activity with IC50 values of 5.43±0.95 and 9.63±1.32 µM, respectively. The aforesaid potent compounds were found effective against SW480 (colorectal adenocarcinoma cells) with IC50 values of 31.44 µM and 106.91 µM, respectively. Compound 5a was found to arrest the cell cycle at the G2/M phase, increasing apoptotic cell death. The docking study also supported VEGFR-2 inhibitory activity as both compounds 5a and 5g displayed promising binding and interactions with the active sites of VEGFR-2 receptor (PDB: 3VHE) with docking scores -9.355 and -7.758, respectively. All the compounds obeyed Lipinski’s rule of five. Conclusion: Indoline-2,3-dione and thiazole have huge potential to be considered a steer combination approach for developing promising kinase inhibitors as cancer therapeutics.

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Perillaldehyde 1,2-epoxide Loaded SLN-Tailored mAb: Production, Physicochemical Characterization and In Vitro Cytotoxicity Profile in MCF-7 Cell Lines

Pharmaceutics ◽

10.3390/pharmaceutics12020161 ◽

2020 ◽

Vol 12 (2) ◽

pp. 161 ◽

Cited By ~ 16

Author(s):

Eliana B. Souto ◽

Selma B. Souto ◽

Aleksandra Zielinska ◽

Alessandra Durazzo ◽

Massimo Lucarini ◽

...

Keyword(s):

Cell Lines ◽

Cetyltrimethylammonium Bromide ◽

Physicochemical Characterization ◽

Thiobarbituric Acid ◽

In Vitro Cytotoxicity ◽

Solid Lipid Nanoparticle ◽

Mab Production ◽

Epithelial Growth ◽

Mcf 7

We have developed a new cationic solid lipid nanoparticle (SLN) formulation, composed of Compritol ATO 888, poloxamer 188 and cetyltrimethylammonium bromide (CTAB), to load perillaldehyde 1,2-epoxide, and surface-tailored with a monoclonal antibody for site-specific targeting of human epithelial growth receptor 2 (HER2). Perillaldehyde 1,2-epoxide-loaded cationic SLN (cPa-SLN), with a mean particle size (z-Ave) of 275.31 ± 4.78 nm and polydispersity index (PI) of 0.303 ± 0.081, were produced by high shear homogenization. An encapsulation efficiency of cPa-SLN above 80% was achieved. The release of perillaldehyde 1,2-epoxide from cationic SLN followed the Korsemeyer–Peppas kinetic model, which is typically seen in nanoparticle formulations. The lipid peroxidation of cPa-SLN was assessed by the capacity to produce thiobarbituric acid-reactive substances, while the antioxidant activity was determined by the capacity to scavenge the stable radical DPPH. The surface functionalization of cPa-SLN with the antibody was done via streptavidin-biotin interaction, monitoring z-Ave, PI and ZP of the obtained assembly (cPa-SLN-SAb), as well as its stability in phosphate buffer. The effect of plain cationic SLN (c-SLN, monoterpene free), cPa-SLN and cPa-SLN-SAb onto the MCF-7 cell lines was evaluated in a concentration range from 0.01 to 0.1 mg/mL, confirming that streptavidin adsorption onto cPa-SLN-SAb improved the cell viability in comparison to the cationic cPa-SLN.

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Synthesis, Antiproliferative Activity and Molecular Docking Studies of Novel Doubly Modified Colchicine Amides and Sulfonamides as Anticancer Agents

Molecules ◽

10.3390/molecules25081789 ◽

2020 ◽

Vol 25 (8) ◽

pp. 1789 ◽

Cited By ~ 2

Author(s):

Julia Krzywik ◽

Witold Mozga ◽

Maral Aminpour ◽

Jan Janczak ◽

Ewa Maj ◽

...

Keyword(s):

Molecular Docking ◽

Cell Lines ◽

Anticancer Agents ◽

Antiproliferative Activity ◽

Docking Studies ◽

Binding Modes ◽

Colchicine Binding Site ◽

3T3 Cell Lines ◽

Colchicine Derivatives

Colchicine is a well-known compound with strong antiproliferative activity that has had limited use in chemotherapy because of its toxicity. In order to create more potent anticancer agents, a series of novel colchicine derivatives have been obtained by simultaneous modification at C7 (amides and sulfonamides) and at C10 (methylamino group) positions and characterized by spectroscopic methods. All the synthesized compounds have been tested in vitro to evaluate their cytotoxicity toward A549, MCF-7, LoVo, LoVo/DX and BALB/3T3 cell lines. Additionally, the activity of the studied compounds was investigated using computational methods involving molecular docking of the colchicine derivatives to β-tubulin. The majority of the obtained derivatives exhibited higher cytotoxicity than colchicine, doxorubicin or cisplatin against tested cancer cell lines. Furthermore, molecular modeling studies of the obtained compounds revealed their possible binding modes into the colchicine binding site of tubulin.

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Design, Synthesis, and Biological Evaluation of Pyridineamide Derivatives Containing a 1,2,3-Triazole Fragment as Type II c-Met Inhibitors

Molecules ◽

10.3390/molecules25010010 ◽

2019 ◽

Vol 25 (1) ◽

pp. 10 ◽

Cited By ~ 1

Author(s):

Hehua Xiong ◽

Jianxin Cheng ◽

Jianqing Zhang ◽

Qian Zhang ◽

Zhen Xiao ◽

...

Keyword(s):

Antitumor Activity ◽

Cell Lines ◽

Inhibitory Activity ◽

Docking Simulation ◽

Binding Mode ◽

Biological Evaluation ◽

Design Synthesis ◽

Ic50 Values ◽

Mcf 7

A series of 4-(pyridin-4-yloxy)benzamide derivatives containing a 1,2,3-triazole fragment were designed, synthesized, and their inhibitory activity against A549, HeLa, and MCF-7 cancer cell lines was evaluated. Most compounds exhibited moderate to potent antitumor activity against the three cell lines. Among them, the promising compound B26 showed stronger inhibitory activity than Golvatinib, with IC50 values of 3.22, 4.33, and 5.82 μM against A549, HeLa, and MCF-7 cell lines, respectively. The structure–activity relationships (SARs) demonstrated that the modification of the terminal benzene ring with a single electron-withdrawing substituent (fluorine atom) and the introduction of a pyridine amide chain with a strong hydrophilic group (morpholine) to the hinge region greatly improved the antitumor activity. Meanwhile, the optimal compound B26 showed potent biological activity in some pharmacological experiments in vitro, such as cell morphology study, dose-dependent test, kinase activity assay, and cell cycle experiment. Finally, the molecular docking simulation was performed to further explore the binding mode of compound B26 with c-Met.

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CYTOTOXIC ACTIVITY OF LUVUNGA SCANDENS AGAINST HUMAN CANCER CELL LINES

Jurnal Teknologi ◽

10.11113/jt.v78.7328 ◽

2016 ◽

Vol 78 (10) ◽

Author(s):

Putri Nur Hidayah Al-Zikri ◽

Muhammad Taher ◽

Deny Susanti ◽

Solachuddin Jauhari Arief Ichwan

Keyword(s):

Cytotoxic Activity ◽

Cell Line ◽

Cell Lines ◽

A549 Cell ◽

Human Cancer ◽

In Vitro Cytotoxicity ◽

Breast Adenocarcinoma ◽

Human Cancer Cell Lines ◽

Mcf 7

Luvunga scandens belongs to the family of Rutaceae which usually inhabit tropical and moist environment. This plant is known as ‘Mengkurat Jakun’ among locals and used traditionally to treat fever and fatigue via decoction. The aim of this study was to investigate the cytotoxic activity of the leaves and stems extracts of L. scandens extract. Extracts of the leaves and stems were obtained from sequential extraction procedures by various organic solvents. All extracts were subjected to cytotoxic study by 3-(4, 5-dimethylthaizol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. In in vitro cytotoxicity assay, all L. scandens extracts exhibited cytotoxicity against human breast adenocarcinoma (MCF-7) and human lung adenocarcinoma (A549) cell lines. The IC50 values of dichloromethane and methanol extracts from the leaves of L. scandens against MCF-7 cell line were 62.5 µg/mL and 88.0 µg/mL, respectively, whereas IC50 of methanol extract from stem was 81.0 µg/mL. All extracts were less active against A549 cell line where IC50 value were not be determined. The present findings revealed the potential of L. scandens as a cytotoxic agent against MCF-7 cell line. However, further studies should be planned to evaluate role of the plant in cytotoxic activity.

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