scholarly journals Design, Synthesis, and Anticancer Effect Studies of Iridium(III) Polypyridyl Complexes against SGC-7901 Cells

Molecules ◽  
2019 ◽  
Vol 24 (17) ◽  
pp. 3129 ◽  
Author(s):  
Li-Xia Zhang ◽  
Yi-Ying Gu ◽  
Yang-Jie Wang ◽  
Lan Bai ◽  
Fan Du ◽  
...  
Keyword(s):  
Dna Damage ◽  
Atp Depletion ◽  
Design Synthesis ◽  
Cycle Arrest ◽  
Mtt Method ◽  
Mitochondrial Membrane Depolarization ◽  
Cell Proliferation Activity ◽  
Ic50 Values ◽  
Nih 3T3

Three iridium(III) complexes ([Ir(Hppy)2(L)](PF6) (Hppy = 2-phenylpyridine, L = 5-nitrophenanthroline, NP), 1; 5-nitro-6-amino-phenanthroline (NAP), 2; and 5,6-diamino-phenanthroline (DAP) 3 were synthesized and characterized. The cytotoxicities of Ir(III) complexes 1–3 against cancer cell lines SGC-7901, A549, HeLa, Eca-109, HepG2, BEL-7402, and normal NIH 3T3 cells were investigated using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide (MTT) method. The results showed that the three iridium(III) complexes had moderate in vitro anti-tumor activity toward SGC-7901 cells with IC50 values of 3.6 ± 0.1 µM for 1, 14.1 ± 0.5 µM for 2, and 11.1 ± 1.3 µM for 3. Further studies showed that 1–3 induce cell apoptosis/death through DNA damage, cell cycle arrest at the S or G0/G1 phase, ROS elevation, increased levels of Ca2+, high mitochondrial membrane depolarization, and cellular ATP depletion. Transwell and Colony-Forming assays revealed that complexes 1–3 can also effectively inhibit the metastasis and proliferation of tumor cells. These results demonstrate that 1–3 induce apoptosis in SGC-7901 cells through ROS-mediated mitochondrial damage and DNA damage pathways, as well as by inhibiting cell invasion, thereby exerting anti-tumor cell proliferation activity in vitro.

scholarly journals Design, Synthesis, and In Vitro/In Vivo Anti-Cancer Activities of Novel (20S)-10,11-Methylenedioxy-Camptothecin Heterocyclic Derivatives

2020 ◽  
Vol 21 (22) ◽  
pp. 8495
Author(s):  
Xiufen Dai ◽  
Guanzhao Wu ◽  
Yixuan Zhang ◽  
Xiaomin Zhang ◽  
Ruijuan Yin ◽  
...  
Keyword(s):  
Water Solubility ◽  
A549 Cells ◽  
Antitumor Efficacy ◽  
Cytotoxic Activities ◽  
Design Synthesis ◽  
Cycle Arrest ◽  
Heterocyclic Derivatives ◽  
Ic50 Values

A novel camptothecin analogue, (20S)-10,11-methylenedioxy-camptothecin (FL118), has been proven to show significant antitumor efficacy for a wide variety of solid tumors. However, the further development of FL118 is severely hindered due to its extremely poor water solubility and adverse side effects. Here, two series of novel 20-substituted (20S)-10,11-methylenedioxy-camptothecin coupled with 5-substituted uracils and other heterocyclic rings through glycine were synthesized. All the derivatives showed superior cytotoxic activities in vitro with IC50 values in the nanomolar range. Among them, 12e displayed higher cytotoxic activities in several cancer cell lines with better water solubility than FL118. Our results further showed that, like FL118, 12e inhibited cell proliferation resulting from cell cycle arrest and apoptosis by blocking the anti-apoptotic gene transcription of survivin, Mcl-1, Bcl-2, and XIAP in both A549 cells and NCI-H446 cells. Furthermore, 12e did not show any inhibitory activity on Topo I, which is involved in hematopoietic toxicity. In vivo, 12e showed similar antitumor efficacy to FL118 but lower toxicity. Our findings indicate that 12e is a promising therapeutic agent for cancer treatment, and the core structure of FL118 represents a promising platform to generate novel FL118-based antitumor drugs.

A Novel Camptothecin Derivative 3j Inhibits Nsclc Proliferation Via Induction of Cell Cycle Arrest By Topo I-Mediated DNA Damage

2019 ◽  
Vol 19 (3) ◽  
pp. 365-374 ◽  
Author(s):  
Yang Liu ◽  
Jingyin Zhang ◽  
Shuyun Feng ◽  
Tingli Zhao ◽  
Zhengzheng Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Flow Cytometry ◽  
Dna Damage ◽  
Cyclin D ◽  
Dna Relaxation ◽  
Cycle Arrest ◽  
H460 Cell ◽  
H1975 Cell

Objective: The aim of this study is to investigate the inhibitory effect of camptothecin derivative 3j on Non-Small Cell Lung Cancer (NSCLCs) cells and the potential anti-tumor mechanisms. Background: Camptothecin compounds are considered as the third largest natural drugs which are widely investigated in the world and they suffered restriction because of serious toxicity, such as hemorrhagic cystitis and bone marrow suppression. Methods: Using cell proliferation assay and S180 tumor mice model, a series of 20(S)-O-substituted benzoyl 7- ethylcamptothecin compounds were screened and evaluated the antitumor activities in vitro and in vivo. Camptothecin derivative 3j was selected for further study using flow cytometry in NSCLCs cells. Cell cycle related protein cyclin A2, CDK2, cyclin D and cyclin E were detected by Western Blot. Then, computer molecular docking was used to confirm the interaction between 3j and Topo I. Also, DNA relaxation assay and alkaline comet assay were used to investigate the mechanism of 3j on DNA damage. Results: Our results demonstrated that camptothecin derivative 3j showed a greater antitumor effect in eleven 20(S)-O-substituted benzoyl 7-ethylcamptothecin compounds in vitro and in vivo. The IC50 of 3j was 1.54± 0.41 µM lower than irinotecan with an IC50 of 13.86±0.80 µM in NCI-H460 cell, which was reduced by 8 fold. In NCI-H1975 cell, the IC50 of 3j was 1.87±0.23 µM lower than irinotecan (IC50±SD, 5.35±0.38 µM), dropped by 1.8 fold. Flow cytometry analysis revealed that 3j induced significant accumulation in a dose-dependent manner. After 24h of 3j (10 µM) treatment, the percentage of NCI-H460 cell in S-phase significantly increased (to 93.54 ± 4.4%) compared with control cells (31.67 ± 3.4%). Similarly, the percentage of NCI-H1975 cell in Sphase significantly increased (to 83.99 ± 2.4%) compared with control cells (34.45 ± 3.9%) after treatment with 10µM of 3j. Moreover, increased levels of cyclin A2, CDK2, and decreased levels of cyclin D, cyclin E further confirmed that cell cycle arrest was induced by 3j. Furthermore, molecular docking studies suggested that 3j interacted with Topo I-DNA and DNA-relaxation assay simultaneously confirmed that 3j suppressed the activity of Topo I. Research on the mechanism showed that 3j exhibited anti-tumour activity via activating the DNA damage response pathway and suppressing the repair pathway in NSCLC cells. Conclusion: Novel camptothecin derivative 3j has been demonstrated as a promising antitumor agent and remains to be assessed in further studies.

Design, synthesis of novel quinazolinone-based oxobutanonitrile derivatives as antiproliferative agents targeting human breast cancer

2021 ◽  
Vol 21 ◽  
Author(s):  
Omaima Mohamed AboulWafa ◽  
Hoda Mohamed Gamal El-Din Daabees ◽  
Eman Salah Ezz-ElDien
Keyword(s):  
Breast Cancer ◽  
Binding Affinities ◽  
Caspase 9 ◽  
Design Synthesis ◽  
Egfr Inhibition ◽  
Cycle Arrest ◽  
M Phase ◽  
Quinazolinone Derivatives ◽  
Mcf 7

Background: Breast cancer (BC) is among the leading causes of death among women worldwide. Medical interest has focused on quinazolinone derivatives approved and utilized in antitumor medications. Objective: Novel quinazolinone-based oxobutanonitrile derivatives were designed, synthesized, and screened for in vitro anti-BC activity. Methods: The antiproliferative activities were determined using MTT assay against MCF-7 and MDA-MB-231 cell lines. EGFR, ARO, and caspase-9 enzymes were selected to explore the mechanism of action of the most potent compounds. Results: Tested compounds showed better EGFRIs than ARIs. In addition, significant overexpression in caspase-9 level in treated MCF-7 breast cell line samples was observed with the most active compounds. The thienyl derivative 5 induced the greatest activation in caspase-9 level in treated MCF-7 breast cancer samples. The o-tolylhydrazone 3b, exhibiting promising ARO inhibition and weak EGFR inhibition, produced a noticeable high overexpression of caspase-9 and showed pre-G1 apoptosis and cell cycle arrest at G2/M phase for MCF-7 cells and at S-phase for MDA-MB-231 cells. Docking results revealed that 3b, elicited binding affinities to ARO comparable to those of letrozole. Conclusion: The obtained results support the therapeutic importance of some of these compounds as anti-BC agents in light of the simple methodology used for their synthesis. Their design offered a way for the optimization and development of apoptotic quinazolinone-based ARO and EGFR inhibitors.

scholarly journals A Nitrocarbazole as a New Microtubule-Targeting Agent in Breast Cancer Treatment

2021 ◽  
Vol 11 (19) ◽  
pp. 9139
Author(s):  
Maria Stefania Sinicropi ◽  
Cinzia Tavani ◽  
Camillo Rosano ◽  
Jessica Ceramella ◽  
Domenico Iacopetta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Anticancer Activity ◽  
Breast Cancer Cell Lines ◽  
Cellular Functions ◽  
Anticancer Properties ◽  
Cycle Arrest ◽  
In Silico Studies ◽  
Ic50 Values ◽  
Mcf 7

Breast cancer is still considered a high-incidence disease, and numerous are the research efforts for the development of new useful and effective therapies. Among anticancer drugs, carbazole compounds are largely studied for their anticancer properties and their ability to interfere with specific targets, such as microtubule components. The latter are involved in vital cellular functions, and the perturbation of their dynamics leads to cell cycle arrest and subsequent apoptosis. In this context, we report the anticancer activity of a series of carbazole analogues 1–8. Among them, 2-nitrocarbazole 1 exhibited the best cytotoxic profile, showing good anticancer activity against two breast cancer cell lines, namely MCF-7 and MDA-MB-231, with IC50 values of 7 ± 1.0 and 11.6 ± 0.8 μM, respectively. Furthermore, compound 1 did not interfere with the growth of the normal cell line MCF-10A, contrarily to Ellipticine, a well-known carbazole derivative used as a reference molecule. Finally, in vitro immunofluorescence analysis and in silico studies allowed us to demonstrate the ability of compound 1 to interfere with tubulin organization, similarly to vinblastine: a feature that results in triggering MCF-7 cell death by apoptosis, as demonstrated using a TUNEL assay.

scholarly journals The Activity of Combination of Hydrolyzed Virgin Coconut Oil and Chitosan Toward Wound Healing Parameters on NIH 3T3 Cells Using in Vitro Methods

1970 ◽  
Vol 7 (3) ◽  
pp. 14-19 ◽  
Author(s):  
Hekdin Marsius Sipayung ◽  
Jansen Silalahi ◽  
Yuandani Y
Keyword(s):  
Cell Proliferation ◽  
Wound Healing ◽  
Protein Expression ◽  
Scratch Wound ◽  
Cell Proliferation Activity ◽  
Proliferation Activity ◽  
Cox 2 ◽  
Nih 3T3 ◽  
Vegf Protein

Objectives: The objective of this study was to investigate the activity of combination of hydrolyzed VCO (HVCO) and chitosan on NIH 3T3 cell proliferation activity, NIH 3T3 cell migration, COX-2 and VEGF protein expression. Design: In vitro cytotoxic assay was determined by MTT (MicrocultureTetrazoliumTehnique) assay, cell proliferation activity was measured by calculating cell viability incubated 24 hours, 48 hours and 72 hours, wound closure percentage was tested by scratch wound healing method, expression of COX-2 protein and VEGF protein were measured by immunocytochemical method. Interventions: The variable that was intervened in this study was the concentration of HVCO and chitosan. Main Outcome Measures: The main measurements carried out in this study were the absorbance value of HVCO and chitosan which was converted into viability cell, proliferation activity, percentage of wound closure, and percentage of COX-2 and VEGF protein expression. Results: Cytotoxic activity of HVCO and chitosan resulted the best concentration at 31.25 μg/ml, scratch wound healing assay from a combination HVCO and chitosan resulted the best migration of fibroblast cells at a ratio of 1:1 with HVCO 62.5 μg/ml and chitosan 62.5 μg/ml, combination of HVCO 62.5 μg/ml and chitosan 62.5 μg/ml (1:1) increased expression of COX-2 and VEGF. Conclusion: Combination of HVCO and chitosan could increase NIH 3T3 cell migration, COX-2 and VEGF protein expression. Combination of HVCO and chitosan had better wound healing activity in vitro than single use. Keywords: Rhizomucor miehei, viability, proliferation, migration, expression

scholarly journals Design, synthesis and pharmacological evaluation of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives as antitumor agents: in vitro and in vivo antitumor activity, cell cycle arrest and apoptotic response

RSC Advances ◽  
2018 ◽  
Vol 8 (43) ◽  
pp. 24376-24385 ◽  
Author(s):  
Wen-Bin Kuang ◽  
Ri-Zhen Huang ◽  
Yi-Lin Fang ◽  
Gui-Bin Liang ◽  
Chen-Hui Yang ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Antitumor Agents ◽  
Quinoline Derivatives ◽  
Apoptotic Response ◽  
Design Synthesis ◽  
Cycle Arrest ◽  
In Vivo Antitumor Activity ◽  
Combination Principle

A series of novel 2-chloro-3-(1H-benzo[d]imidazol-2-yl)quinoline derivatives were designed and synthesized as antitumor agents under the combination principle. The antitumor activity and mechanisms were then evaluated.

scholarly journals Protoflavone-Chalcone Hybrids Exhibit Enhanced Antitumor Action through Modulating Redox Balance, Depolarizing the Mitochondrial Membrane, and Inhibiting ATR-Dependent Signaling

Antioxidants ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 519 ◽  
Author(s):  
Ahmed Dhahir Latif ◽  
Tamás Jernei ◽  
Ana Podolski-Renić ◽  
Ching-Ying Kuo ◽  
Máté Vágvölgyi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mitochondrial Membrane ◽  
Redox Balance ◽  
Breast Cancer Cell Lines ◽  
Antitumor Action ◽  
Hybrid Compounds ◽  
Mitochondrial Membrane Depolarization ◽  
Ic50 Values ◽  
Novel Strategy

Hybrid compounds combine fragments with complementary targets to achieve a common pharmacological goal. This approach represents an increasingly popular strategy for drug discovery. In this work, we aimed to design antitumor hybrid compounds based on an inhibitor of ataxia-telangiectasia and Rad3-related protein (ATR)-dependent signaling, protoapigenone, and a pro-oxidant ferrocene or chalcone fragment. Four new triazole-coupled hybrids were prepared. The compounds were cytotoxic against human breast cancer cell lines in vitro, showing IC50 values in the sub-micromolar range. The nature of interactions between relevant fragments of the hybrids was evaluated by the Chou–Talalay method. Experimental combination treatment with the fragments showed additive effects or slight/moderate synergism, while strong synergism was observed when the fragments were virtually combined into their hybrids, suggesting a relevant pharmacological benefit of the coupling. All hybrids were strong inhibitors of the ATR-mediated activation of Chk1, and they interfered with the redox balance of the cells leading to mitochondrial membrane depolarization. Additionally, they induced late apoptosis and primary necrosis in MDA-MB-231 and MCF-7 breast cancer cells, respectively. Our results demonstrate that coupling the ATR-dependent signaling inhibitor protoflavone with a pro-oxidant chalcone dramatically increases the antitumor activity compared with either fragment alone. Such compounds may offer an attractive novel strategy for the treatment of various cancers.

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

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 10 ◽  
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.

scholarly journals Virtual Screening Guided Design, Synthesis and Bioactivity Study of Benzisoselenazolones (BISAs) on Inhibition of c-Met and Its Downstream Signalling Pathways

2019 ◽  
Vol 20 (10) ◽  
pp. 2489 ◽  
Author(s):  
Siqi Zhang ◽  
Qiaoling Song ◽  
Xueting Wang ◽  
Zhiqiang Wei ◽  
Rilei Yu ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Cancer Cell ◽  
Kinase Inhibitors ◽  
Antitumour Activity ◽  
Cancer Cell Line ◽  
Lung Cancer Cell Line ◽  
Signalling Pathways ◽  
Design Synthesis ◽  
Ic50 Values

c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In this study, we designed a small library containing 300 BISAs molecules that consisted of carbohydrates, amino acids, isothiourea, tetramethylthiourea, guanidine and heterocyclic groups and screened c-Met targeting compounds using docking and MM/GBSA. Guided by virtual screening, we synthesised a series of novel compounds and their activity on inhibition of the autophosphorylation of c-Met and its downstream signalling pathway proteins were evaluated. We found a panel of benzisoselenazolones (BISAs) obtained by introducing isothiourea, tetramethylthiourea and heterocyclic groups into the C-ring of Ebselen, including 7a, 7b, 8a, 8b and 12c (with IC50 values of less than 20 μM in MET gene amplified lung cancer cell line EBC-1), exhibited more potent antitumour activity than Ebselen by cell growth assay combined with in vitro biochemical assays. In addition, we also tested the antitumour activity of three cancer cell lines without MET gene amplification/activation, including DLD1, MDA-MB-231 and A549. The neuroblastoma SK-N-SH cells with HGF overexpression which activates MET signalling are sensitive to MET inhibitors. The results reveal that our compounds may be nonspecific multitarget kinase inhibitors, just like type-II small molecule inhibitors. Western blot analysis showed that these inhibitors inhibited autophosphorylation of c-MET, and its downstream signalling pathways, such as PI3K/AKT and MARK/ERK. Results suggest that bensoisoselenones can be used as a scaffold for the design of c-Met inhibiting drug leads, and this study opens up new possibilities for future antitumour drug design.

scholarly journals PHF2 histone demethylase prevents DNA damage and genome instability by controlling cell cycle progression of neural progenitors

2019 ◽  
Vol 116 (39) ◽  
pp. 19464-19473 ◽  
Author(s):  
Stella Pappa ◽  
Natalia Padilla ◽  
Simona Iacobucci ◽  
Marta Vicioso ◽  
Elena Álvarez de la Campa ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Genome Stability ◽  
Cell Cycle Progression ◽  
Genome Instability ◽  
Neural Progenitors ◽  
Cycle Progression ◽  
Cycle Arrest ◽  
Biochemical Assays

Histone H3 lysine 9 methylation (H3K9me) is essential for cellular homeostasis; however, its contribution to development is not well established. Here, we demonstrate that the H3K9me2 demethylase PHF2 is essential for neural progenitor proliferation in vitro and for early neurogenesis in the chicken spinal cord. Using genome-wide analyses and biochemical assays we show that PHF2 controls the expression of critical cell cycle progression genes, particularly those related to DNA replication, by keeping low levels of H3K9me3 at promoters. Accordingly, PHF2 depletion induces R-loop accumulation that leads to extensive DNA damage and cell cycle arrest. These data reveal a role of PHF2 as a guarantor of genome stability that allows proper expansion of neural progenitors during development.

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