Synthesis and Antiproliferative Activity of Novel Neocryptolepine-Hydrazides Hybrids

A new series of flurbiprofen derivatives containing thiosemicarbazide moiety (3-7) was synthesized from flurbiprofen as parent nucleus by esterification, hydrazide formation, and heating with different aryl isothiocyanate substituents, respectively. Flurbiprofen was also treated with thiosemicarbazide in the presence POCl3 as a catalyst, to produce 1,3,4 -thiadiazole -2-amine (8). Treatment of (8) with different aryl isothiocyanates produced thiourea derivatives (9-12). Also, the reaction of (8) with different benzoyl chloride substituents produced benzamide compounds (13-15). Eventually , treatment of (8) with ethyl acetoacetate(EAA) produced [1,3,4]thiadiazolo[3,2-a]pyrimidin-7-one (16) .The new compounds were characterized by spectroscopic techniques :FTIR, 1HNMR, and CHNS analysis. A molecular docking study for the synthesized compounds (3-16), against the Vascular Endothelial Growth Factor receptor (VEGFR-2) was applied and it indicated that compounds 4,7,13, and 15,exhibited the optimum binding energy of -6.77, -6.12,-6.68, and -6.43 kcal/mol, respectively. Target compounds were also assessed for their in vitro anticancer effects in a cell-line study. All of the compounds tested showed the most plausible anticancer activity, compared to a positive control(Sorafenib), using in vitro MTT cytotoxic assay ,against human breast tumor (MCF-7), and normal WRL-68 cell line. The in vitro results revealed that compounds 4,5,10,11,13, and 15 exhibited the highest inhibitory activity at their IC50 concentrations, against MCF-7 cell lines, as follows (122.7,113.9,95,7. 109.1,40.32 and 112.29µg/mL, respectively. While their cytotoxic effect against normal WRL-68 cell line at their IC50 concentrations, as follow 210.2, 181.3 ,151.7,278.7,80.28, and 236 µg/mL, respectively, therefore, such compounds were considered more selective toward MCF-7 than normal WRL-68,and their selectivity index (SI): 1.71,1.59,1.59 ,2.55 ,1.99 , and 2.10,respectively . Among the synthesized compounds, the compound 15 was chosen to screen its effect in vitro through multi-parameter cytotoxic assay against MCF-7 breast cancer implemented in High Content Screening (ArrayScan XTI, Thermo Scientific),which could be taken in consideration as a starting point for the development of new anticancer drugs

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“…The study of MTT and HCS was carried out using the procedure outlined earlier in the literature (Sebeka et al, 2017;El-Far et al,2009).…”

Section: Biological Screeningmentioning

confidence: 99%

Am Synthesis, Docking Study and In vitro Anticancer Evaluation of Some New Flurbiprofen Derivatives Against MCF-7 and WRL-68 Cell Lines

et al. 2021

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“…To evaluate the potential cytotoxic effect of the R. nomadica venom on cell viability, an MTT (3-(4, 5-methylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide) reduction assay was performed [61,62]. HepG2, MDA-MB-231, HFB4, and WI-38 cells (VACSERA, Giza, Egypt) were seeded in a 96-well plate at a concentration of 1.0 × 10 4 cells/well and incubated at 37 • C for 24 h to settle down.…”

Section: Cell Viability By Mtt Assaymentioning

confidence: 99%

Nomad Jellyfish Rhopilema nomadica Venom Induces Apoptotic Cell Death and Cell Cycle Arrest in Human Hepatocellular Carcinoma HepG2 Cells

et al. 2021

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Jellyfish venom is a rich source of bioactive proteins and peptides with various biological activities including antioxidant, antimicrobial and antitumor effects. However, the anti-proliferative activity of the crude extract of Rhopilema nomadica jellyfish venom has not been examined yet. The present study aimed at the investigation of the in vitro effect of R. nomadica venom on liver cancer cells (HepG2), breast cancer cells (MDA-MB231), human normal fibroblast (HFB4), and human normal lung cells (WI-38) proliferation by using MTT assay. The apoptotic cell death in HepG2 cells was investigated using Annexin V-FITC/PI double staining-based flow cytometry analysis, western blot analysis, and DNA fragmentation assays. R. nomadica venom displayed significant dose-dependent cytotoxicity on HepG2 cells after 48 h of treatment with IC50 value of 50 μg/mL and higher toxicity (3:5-fold change) against MDA-MB231, HFB4, and WI-38 cells. R. nomadica venom showed a prominent increase of apoptosis as revealed by cell cycle arrest at G2/M phase, upregulation of p53, BAX, and caspase-3 proteins, and the down-regulation of anti-apoptotic Bcl-2 protein and DNA fragmentation. These findings suggest that R. nomadica venom induces apoptosis in hepatocellular carcinoma cells. To the best of the authors’ knowledge, this is the first scientific evidence demonstrating the induction of apoptosis and cell cycle arrest of R. nomadica jellyfish venom.

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“…This linkage influences the majority of their reactions and properties [13]. The derivatives of hydrazone have been demonstrated to display diverse biological activities which include α-glucosidase inhibition [33,41], antibacterial and anti-fungi [4,14,16,32,34], anticancer [18,38], antitumor [32], anticonvulsant [11], anticholinesterase [20] and antioxidant [3,7,12,15,19,23] activities. Recently, hydrazone derivatives have been employed as corrosion inhibitors for mild steel and iron [10,21].…”

Section: Introductionmentioning

confidence: 99%

In silico design of hydrazone antioxidants and analysis of their free radical-scavenging mechanism by thermodynamic studies

Alisi¹,

Uzairu

Abechi

2019

Beni-Suef Univ J Basic Appl Sci

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Background: Antioxidants are very crucial in maintaining the normal function of body cells, as they scavenge excess free radical in the body. A set of hydrazone antioxidants was designed by in silico screening. The density functional theory (DFT) method was employed to explore the reaction energetics of their free radicalscavenging mechanism. With the aid of the developed quantitative structure-activity relationship (QSAR) model for hydrazone antioxidants, the structure and antioxidant activity of these compounds were predicted. Three potential reaction mechanisms were investigated, namely, hydrogen atom transfer (HAT), single-electron transfer followed by proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET). Bond dissociation enthalpy (BDE), adiabatic ionization potential (AIP), proton dissociation enthalpy (PDE), proton affinity (PA), electron transfer enthalpy (ETE) and Gibbs free energy that characterize the various steps in these mechanisms were calculated in the gas phase. Results: A total of 25 hydrazone antioxidants were designed, in which the molecule MHD 017 gave the best antioxidant activity. Among the tested molecules, MHD 017 at the 10-OH site gave the best results for the various thermodynamic parameters calculated. The reaction Gibbs free energy results also indicate that this is the most favoured site for free radical scavenge. Conclusion: The obtained results show that HAT and SPLET mechanisms are the thermodynamically plausible reaction pathways of free radical scavenge by hydrazone antioxidants. The reactivity of these compounds towards the hydroperoxyl radical (HOO•) was greater than that towards the methyl peroxyl radical (CH 3 OO•) based on the exergonicity of the calculated reaction Gibbs free energy.

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Synthesis and Antiproliferative Activity of Novel Neocryptolepine-Hydrazides Hybrids

Cited by 5 publications

References 17 publications

Am Synthesis, Docking Study and In vitro Anticancer Evaluation of Some New Flurbiprofen Derivatives Against MCF-7 and WRL-68 Cell Lines

Am Synthesis, Docking Study and In vitro Anticancer Evaluation of Some New Flurbiprofen Derivatives Against MCF-7 and WRL-68 Cell Lines

Nomad Jellyfish Rhopilema nomadica Venom Induces Apoptotic Cell Death and Cell Cycle Arrest in Human Hepatocellular Carcinoma HepG2 Cells

In silico design of hydrazone antioxidants and analysis of their free radical-scavenging mechanism by thermodynamic studies

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