Synthesis of 1,2,3‐Triazolo‐fused‐tetrahydro‐β‐carboline Derivatives via 1,3‐Dipolar Cycloaddition Reaction: Cytotoxicity Evaluation and DNA‐Binding studies

Nekkanti, Shalini; Pooladanda, Venkatesh; Veldandi, Mamatha; Tokala, Ramya; Godugu, Chandraiah; Shankaraiah, Nagula

doi:10.1002/slct.201700620

Cited by 25 publications

(17 citation statements)

References 61 publications

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“…Cell viability was determined by MTT assay as described previously with slight modifications 17 . Here, the cells were seeded in 96-well plate and treated with nimbolide (0.5-10 µM) for 24 h. Then cells were washed with PBS and MTT (0.5 mg/ml) was added to each well, followed by formazan crystals were solubilized with DMSO and absorbance was measured at 570 nm with the spectrophotometer (Spectra Max, M4 Molecular devices, USA).…”

Section: Methodsmentioning

confidence: 99%

Nimbolide protects against endotoxin-induced acute respiratory distress syndrome by inhibiting TNF-α mediated NF-κB and HDAC-3 nuclear translocation

et al. 2019

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Acute respiratory distress syndrome (ARDS) is characterized by an excessive acute inflammatory response in lung parenchyma, which ultimately leads to refractory hypoxemia. One of the earliest abnormalities seen in lung injury is the elevated levels of inflammatory cytokines, among them, the soluble tumor necrosis factor (TNF-α) has a key role, which exerts cytotoxicity in epithelial and endothelial cells thus exacerbates edema. The bacterial lipopolysaccharide (LPS) was used both in vitro (RAW 264.7, THP-1, MLE-12, A549, and BEAS-2B) and in vivo (C57BL/6 mice), as it activates a plethora of overlapping inflammatory signaling pathways involved in ARDS. Nimbolide is a chemical constituent of Azadirachta indica, which contains multiple biological properties, while its role in ARDS is elusive. Herein, we have investigated the protective effects of nimbolide in abrogating the complications associated with ARDS. We showed that nimbolide markedly suppressed the nitrosative-oxidative stress, inflammatory cytokines, and chemokines expression by suppressing iNOS, myeloperoxidase, and nitrotyrosine expression. Moreover, nimbolide mitigated the migration of neutrophils and mast cells whilst normalizing the LPS-induced hypothermia. Also, nimbolide modulated the expression of epigenetic regulators with multiple HDAC inhibitory activity by suppressing the nuclear translocation of NF-κB and HDAC-3. We extended our studies using molecular docking studies, which demonstrated a strong interaction between nimbolide and TNF-α. Additionally, we showed that treatment with nimbolide increased GSH, Nrf-2, SOD-1, and HO-1 protein expression; concomitantly abrogated the LPS-triggered TNF-α, p38 MAPK, mTOR, and GSK-3β protein expression. Collectively, these results indicate that TNF-α-regulated NF-κB and HDAC-3 crosstalk was ameliorated by nimbolide with promising anti-nitrosative, antioxidant, and anti-inflammatory properties in LPS-induced ARDS.

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Section: Methodsmentioning

confidence: 99%

Nimbolide protects against endotoxin-induced acute respiratory distress syndrome by inhibiting TNF-α mediated NF-κB and HDAC-3 nuclear translocation

et al. 2019

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“…HaCaT cells were cultured and treated with PPL for 2 h and incubated with EGF for 48 h. Later, the cells were collected by trypsinization and fixed in 70% ethanol and stored at −20°C. Later, cells were washed with PBS and incubated with PI staining buffer (a mixture of PI, triton-X-100, RNAse enzyme, and double distilled water) for 15 min and then subjected to flow cytometric analysis (BD C6 Accuri flow cytometry, USA) 67 .…”

Section: Determination Of Cell Cycle Analysismentioning

confidence: 99%

Piperlongumine regulates epigenetic modulation and alleviates psoriasis-like skin inflammation via inhibition of hyperproliferation and inflammation

et al. 2020

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Psoriasis is an autoimmune skin disease, where chronic immune responses due to exaggerated cytokine signaling, abnormal differentiation, and evasion of keratinocytes apoptosis plays a crucial role in mediating abnormal keratinocytes hyperproliferation. From the therapeutic perspective, the molecules with strong anti-proliferative and anti-inflammatory properties could have tremendous relevance. In this study, we demonstrated that piperlongumine (PPL) treatment effectively abrogated the hyperproliferation and differentiation of keratinocytes by inducing ROSmediated late apoptosis with loss of mitochondrial membrane potential. Besides, the arrest of cell cycle was found at Sub-G1 phase as a result of DNA fragmentation. Molecularly, inhibition of STAT3 and Akt signaling was observed with a decrease in proliferative markers such as PCNA, ki67, and Cyclin D1 along with anti-apoptotic Bcl-2 protein expression. Keratin 17 is a critical regulator of keratinocyte differentiation, and it was found to be downregulated with PPL significantly. Furthermore, prominent anti-inflammatory effects were observed by inhibition of lipopolysaccharide (LPS)/Imiquimod (IMQ)-induced p65 NF-κB signaling cascade and strongly inhibited the production of cytokine storm involved in psoriasis-like skin inflammation, thus led to the restoration of normal epidermal architecture with reduction of epidermal hyperplasia and splenomegaly. In addition, PPL epigenetically inhibited histone-modifying enzymes, which include histone deacetylases (HDACs) of class I (HDAC1-4) and class II (HDAC6) evaluated by immunoblotting and HDAC enzyme assay kit. In addition, our results show that PPL effectively inhibits the nuclear translocation of p65 and a histone modulator HDAC3, thus sequestered in the cytoplasm of macrophages. Furthermore, PPL effectively enhanced the protein-protein interactions of HDAC3 and p65 with IκBα, which was disrupted by LPS stimulation and were evaluated by Co-IP and molecular modeling. Collectively, our findings indicate that piperlongumine may serve as an anti-proliferative and anti-inflammatory agent and could serve as a potential therapeutic option in treating psoriasis.

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“…Intercalation of a compound into DNA results in an increase in the relative viscosity owing to an increase in the axial length of the DNA helix to naturalize the hybrid. EtBr is a classically measured DNA intercalator that corresponds to an increase in viscosity . Covalent binding to DNA ends up in a decrease in the relative viscosity values, whereas no or little change is observed in the case of groove binding .…”

Section: Resultsmentioning

confidence: 99%

Design and Synthesis of DNA‐Interactive β‐Carboline–Oxindole Hybrids as Cytotoxic and Apoptosis‐Inducing Agents

et al. 2018

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A new series of (E)-3-[(1-aryl-9H-pyrido[3,4-b]indol-3-yl)methylene]indolin-2-one hybrids were synthesized and evaluated for their in vitro cytotoxic activity against a panel of selected human cancer cell lines, namely, HCT-15, HCT-116, A549, NCI-H460, and MCF-7, including HFL. Among the tested compounds, (E)-1-benzyl-5-bromo-3-{[1-(2,5-dimethoxyphenyl)-9H-pyrido[3,4-b]indol-3-yl]methylene}indolin-2-one (10 s) showed potent cytotoxicity against HCT-15 cancer cells with an IC value of 1.43±0.26 μm and a GI value of 0.89±0.06 μm. Notably, induction of apoptosis by 10 s on the HCT-15 cell line was characterized by using different staining techniques, such as acridine orange/ethidium bromide (AO/EB) and DAPI. Further, to understand the mechanism of anticancer effects, various assays such as annexin V-FITC/PI, DCFDA, and JC-1were performed. The flow cytometric analysis revealed that compound 10 s arrests the HCT-15 cancer cells at the G0/G1 phase of the cell cycle. Additionally, western blot analysis indicated that treatment of 10 s on HCT-15 cancer cells led to decreased expression of anti-apoptotic Bcl-2 and increased protein expression of both pro-apoptotic Bax and caspase-3, -8, and -9, and cleaved PARP with reference to actin. Next, a clonogenic assay revealed the inhibition of colony formation in HCT-15 cancer cells by 10 s in a dose-dependent manner. Moreover, upon testing on normal human lung cells (HFL), the compounds were observed to be safer with a low toxicity profile. In addition, viscosity and molecular-docking studies showed that compound 10 s has typical intercalation with DNA.

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Synthesis of 1,2,3‐Triazolo‐fused‐tetrahydro‐β‐carboline Derivatives via 1,3‐Dipolar Cycloaddition Reaction: Cytotoxicity Evaluation and DNA‐Binding studies

Cited by 25 publications

References 61 publications

Nimbolide protects against endotoxin-induced acute respiratory distress syndrome by inhibiting TNF-α mediated NF-κB and HDAC-3 nuclear translocation

Nimbolide protects against endotoxin-induced acute respiratory distress syndrome by inhibiting TNF-α mediated NF-κB and HDAC-3 nuclear translocation

Piperlongumine regulates epigenetic modulation and alleviates psoriasis-like skin inflammation via inhibition of hyperproliferation and inflammation

Design and Synthesis of DNA‐Interactive β‐Carboline–Oxindole Hybrids as Cytotoxic and Apoptosis‐Inducing Agents

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