Reference Drug Doxorubicin Research Articles

A Novel Phosphonates Synthesized from Schiff's Base Indenoquinoxaline Derivatives and its Biological Activity

AbstractIn this study we made of reaction of 11H‐indeno[1,2‐b]quinoxalin‐11‐one with hydrazine hydrate and phenyl hydrazine to afford the corresponding hydrazineylidenes 3 a, b in good yield.A series of a novel Schiff's bases of isatin and aldehydes were synthesized by condensation of them with 11‐hydrazineylidene‐11H‐indeno[1,2‐b]quinoxaline. A number of aminophosphonates were synthesized by reaction of imines with dialkyl phosphites according to Pudovik reaction. The chemical structures of the synthesized compounds were confirmed by means spectroscopic evidences. The cytotoxic activity of ten derivatives were investigated in the liver cancer cell line HepG‐2 and the breast cancer cell line MCF‐7.Compounds 7 a, b showed higher cytotoxicity towards the liver cancer cell line HepG‐2 and compound 10 a gave higher cytotoxicity towards the breast cancer cell line (MCF7) most than the reference drug (Doxorubicin). From the above‐mentioned results it may be concluded that compounds containing bis‐aminophosphonate exhibit better activity than the aminophosphonate. The molecular docking studies of phosphonates and bisphosphonates were investigated.

Diverse Biological Activity of Benzofuroxan/Sterically Hindered Phenols Hybrids.

Combining two pharmacophores in a molecule can lead to useful synergistic effects. Herein, we show hybrid systems that combine sterically hindered phenols with dinitrobenzofuroxan fragments exhibit a broad range of biological activities. The modular assembly of such phenol/benzofuroxan hybrids allows variations in the phenol/benzofuroxan ratio. Interestingly, the antimicrobial activity only appears when at least two benzofuroxan moieties are introduced per phenol. The most potent of the synthesized compounds exhibit high cytotoxicity against human duodenal adenocarcinoma (HuTu 80), human breast adenocarcinoma (MCF-7), and human cervical carcinoma cell lines. This toxicity is associated with the induction of apoptosis via the internal mitochondrial pathway and an increase in ROS production. Encouragingly, the index of selectivity relative to healthy tissues exceeds that for the reference drugs Doxorubicin and Sorafenib. The biostability of the leading compounds in whole mice blood is sufficiently high for their future quantification in biological matrices.

Arylidine extensions of 3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-benzenesulfonamide derivatives: Synthesis, computational simulations and biological evaluation as tumor-associated carbonic anhydrase inhibitors

Several pyrazole-benzene sulfonamides were reported as human carbonic anhydrase inhibitors. In this research work, a design of Arylidine-extented 5-oxo-pyrazole benzenesulfonamides (4a-i), (8a-d) and (10a-e) were reported based on tail-approach design. Beside the reported synthetic procedures and confirmation by different analytical procedures, a DFT study was employed to confirm the Z- conformer of the synthesized compounds. In vitro biological assay against four different human carbonic anhydrases took place and based on the results, SAR study was illustrated and selectivity indexes were discussed. Compounds 4g and 8a exhibited the best inhibitory activity among the target compounds with values (hCAIX: KI = 71.2 nM, hCAXII: KI = 22.5 nM), (hCAIX: KI = 34.3 nM, hCAXII: KI = 74.3 nM); respectively. Both of them were subjected to cellular assay against two different cancer cell lines with expressing nature to hCA isoforms under both normoxic and hypoxic conditions. Compound 4g showed the highest cytotoxic activity against MCF-7 cancer cell line (IC50 = 4.15 µM under hypoxic conditions and IC50 = 8.59 µM under normoxic conditions) compared to the reference drug doxorubicin under normoxic, (IC50 = 4.34 µM), and hypoxic, (IC50 = 2.23 µM), conditions. Further cellular investigations were employed to study the effect of this compound on the cell cycle of the affected cell line. Finally, molecular docking supported by molecular dynamic simulation was utilized to understand the mechanism of the inhibitory activity of two of these compounds – as representative examples- based on the designed rational.

Synthesis, characterization, molecular docking and in vitro anti-cancer activity studies of new and highly selective 1,2,3-triazole substituted 4-hydroxybenzohyrdazide derivatives

In this study, 16 new hybrid compounds 6(a-h) and 7(a-h) were synthesized starting from methylparaben. These new compounds consist of eight 1,2,3-triazole-arylidenehydrazide derivatives and eight 1,2,3-triazole-thiazolidin-4-one derivatives. All compounds were tested against MCF-7 breast cancer cells and MCF10A breast healthy tissue to determine their anti-cancer activity. Molecular docking studies were also carried out against receptor proteins (HER2, EGFR, and VEGFR1) that are related to the growth factor of cancer cells to understand the inhibition mechanism. According to the results of in silico and in vitro activity studies, compounds 6g and 7g were found as the highest selective and active against breast cancer cells.The IC50 values of compounds 6g and 7g against MCF7 cells were found as 8.48 and 4.38 µM, respectively. In addition, the IC50 values of compounds 6g and 7g against MCF10A cells were found as 114.80 and 170.60 µM. When comparing the selectivity of the 6g and 7g to the reference drug doxorubicin, 6g and 7g had higher selectivity (13.5 and 39 respectively) compared to doxorubicin (4). The compound 7g also showed activity against cancer cells at lower doses and was found to be safe against healthy cells at high doses. Molecular docking results showed that both 6g and 7g had higher binding scores for all 3 target enzymes and especially for HER2 protein related to breast cancer with binding scores of -8.059 kcal and -9,008 kcal respectively, while doxorubicin had a binding score of -7.854 kcal. According to the results of the in vitro, and in silico study, compound 7g which was synthesized in this study is a promising, potent, and selective anti-cancer drug candidate for the treatment of breast cancer. All the tested compounds were very well characterized by spectroscopic methods and they have at least 95% HPLC purity.

Synthesis, Characterization and Biological Evaluation of Novel Methoxy Benzaldehyde Substituted Derivatives of Pyrazolopyrimidine-4-hydrazide

Several novel pyrrolopyrimidine derivatives of methoxybenzaldehydes with biologically active pyrrole moieties were synthesized to investigate their antibacterial, antifungal and cytotoxic activities. Elemental analysis, UV-spectra, FT-IR, 1H NMR and 13C NMR spectra, were used to characterize the synthesized compounds. The in vitro antifungal and antibacterial activities were tested for all the synthesized compounds. Compared to the reference drugs e.g. fluconazole and streptomycin, most of the compounds tested positive for antifungal and antibacterial activity. All tested compounds demonstrated superior cytotoxic activity to the reference drug doxorubicin, with IC50 values ranging from 6.52 to 7.77 mM and comparable activity with IC50 values of 8.21 and 8.27 mM, respectively. In vitro antibacterial and antifungal activities revealed that the compouds b and e were more effective than the standard drugs streptomycin and fluconazole, respectively.

Synthesis and Antiproliferative Screening of Some Heterocycles Derived from 4-((5-Chloro-3-Methyl-1-Phenyl-1H-Pyrazol-4-yl)Methylene)-2-Phenyloxazol-5(4H)-One

A new series of pyrazole derivatives was synthesized starting from the pyrazole-based oxazolone derivative 3. The activity of compound 3 toward some mono- and bidentate nucleophiles was investigated. Some of the synthesized compounds were screened for their antiproliferative activity against colon and breast cancer cell lines. The results of the biological assay revealed that the triazinone derivative 13 was the most potent against the two HCT116 and MCF7 cell lines since it showed IC50 = 8.37 ± 0.5 µM and 3.81 ± 0.2 µM, respectively, as compared to the reference drug doxorubicin (IC50 = 5.23 ± 0.3 and 4.17 ± 0.2 µM, respectively).

Novel psoralen derivatives as anti-breast cancer agents and their light-activated cytotoxicity against HER2 positive breast cancer cells

Psoralen derivatives are well known for their unique phototoxicity and also exhibits promising anti-breast cancer activity both in the presence and the absence of UVA irradiation. However, the structure–activity relationship on this scaffold remains lacking. Herein, a series of psoralen derivatives with various C-5 substituents were synthesized and evaluated for their in vitro dark and light-activated cytotoxicity against three breast cancer cell lines: MDA-MB-231, T47-D, and SK-BR-3. The type of substituents dramatically impacted the activity, with the 4-bromobenzyl amide derivative (3c) exhibiting the highest dark cytotoxicity against T47-D (IC50 = 10.14 µM), with the activity comparable to those of the reference drugs (doxorubicin, 1.46 µM; tamoxifen citrate, 20.86 µM; lapatinib 9.78 µM). On the other hand, the furanylamide 3g exhibits the highest phototoxicity against SK-BR-3 cells with the IC50 of 2.71 µM, which is almost tenfold increase compared to the parent compound, methoxsalen. Moreover, these derivatives showed exceptional selectivity towards HER2+ (SK-BR-3) over the HER2− (MDA-MB-231) breast cancer cell lines, which correlates well with the results from the molecular docking study, revealing that 3g formed favorable interactions within the active site of the HER2. Additionally, the cell morphology of SK-BR-3 cells suggested that the significant phototoxicity was related to induction of cell apoptosis. Most of the synthesized psoralen derivatives possess acceptable physicochemical properties and are suitable for being further developed as a novel anti-breast cancer agent in the future.

New benzimidazole based hybrids: Synthesis, molecular modeling study and anticancer evaluation as TopoII inhibitors

Three series of new benzimidazole hybrids were designed and synthesized as promising human TopoII inhibitors. They were characterized by different spectroscopic techniques (1H, 13C NMR, ESI-MS and IR). All hybrids (6–23) were screened for their in vitro antiproliferative activity against five human cancer cell lines namely; HepG-2, MCF-7, PC-3, HCT-116 and Hela. Compound 21 showed the most potent anticancer activity against all cancer cell lines, with IC50 range of 2.82 to 12.59 µM, while proving safe towards normal cells WI-38 (IC50 = 31.89 µM) compared to the reference drug doxorubicin (IC50 = 6.72 µM). The most active candidates 13, 20, 21, 22 and 23 were further assessed for their human TopoII inhibition. The best of which, compounds 13 and 20 showed IC50 of 6.72 and 8.18 µM respectively compared to staurosporine (IC50 = 4.64 µM). Further mechanistic studies for compound 13 showed cell cycle arrest at S-phase by 51.29 % and a significant increase in the total apoptosis by 62.5 folds. Furthermore, apoptosis study proved that it induced apoptosis by decreasing both IAP and Bcl-2, activating caspases 3, 8 and 9, and increasing accumulation of ROS in HepG-2 cells. Besides, it decreased transcription factors’ binding activity to DNA. Comparative molecular docking study was performed between the most potent TopoII inhibitors 13 and 20, and the least potent one 23 to relate the binding pattern with TopoII catalytic active site to the biological activity, where all results came in agreement with the biological results. Additional molecular modeling studies including surface mapping and contact preferences were performed to emphasize the importance of hydrophobicity. Physicochemical calculations were assessed where compounds 13 and 20 represented very promising orally active drug candidates.

Frankincense essential oil nanoemulsion specifically induces lung cancer apoptosis and inhibits survival pathways

BackgroundThe volatile fraction of frankincense (Boswellia sacra) oleogum was extracted, formulated in nanoemulsion and tested against lung cancer A549 cell line. First, the gum was hydro-distilled to isolate the volatile fraction (essential oil), which was analyzed via gas chromatography to identify its major volatile constituents. Then, the oil was formulated in two water-based nanoemulsions which differ from one another in the presence of propylene glycol (PG), which is used in the formulation step as a co-surfactant. The pure essential oil as well as its major volatile compound (α-pinene), its two nanoemulsions and a reference drug (Doxorubicin) were evaluated against lung cancer A549 cell lines and WI-38 normal lung cells. The evaluation included cytotoxicity (MTT and IC50), apoptosis (flow cytometric analysis) in addition to genetic assessments for some intrinsic and extrinsic genes relevant to apoptosis and survival pathways.ResultsChromatographic analysis of frankincense essential oil revealed that α-pinene is the major volatile compound which constituent about 60% of that oil. Emulsification of the oil using the low energy technique gave nanoemulsions having major intense particles population (85–90%) with z-average diameter below 20.0 nm. Frankincense oil nanoemulsion fabricated with (PG) showed the best cytotoxic activity toward lung cancer A549 cell compared to PG-free nanoemulsion, α-pinene and the reference drug doxorubicin, along different incubation periods. Flow cytometric analysis also indicated that PG-containing nanoemulsion can induce cancer cells toward apoptosis better than the other formula and the pure oils. The same nanoemulsion was found to upregulate the pro-apoptotic genes [DR5, FAAD, Caspase 8 (Cas8), p53, and Bax] and downregulate the anti-apoptotic and reoccurrence genes (Bcl-2, NF-kB, and STAT-3). Most importantly, the PG-containing nanoemulsion had the least cytotoxic effect on the normal WI-38 lung cells.ConclusionsThese results point out to the potentials of frankincense essential oil (rich in α-pinene) and its PG-nanoemulsion as a promising adjuvant from plant-source to potentiate the activity of the systematic anti-lung cancer drugs.

Cytotoxicity, acute and sub-chronic toxicities of the fruit extract of Tetrapleura tetraptera (Schumm. & Thonn.) Taub. (Fabaceae)

BackgroundTetrapleura tetraptera is a medicinal spice traditionally used to treat cancer, diabetes, and several other ailments. This study analyzed the cytotoxicity of the dichloromethane methanol extract of T. tetraptera fruits (TTF) and its constituents. The toxicity profile of the TTF extract was also evaluated in rats.MethodsThe Cytotoxicity of this extract was evaluated using the resazurin reduction assay (RRA). Acute and sub-chronic toxicity studies were performed according to the protocol described by the Organisation for Economic Cooperation, and Development (OECD). Hematological, serum, and urine biochemical parameters, as well as histological sections of the liver and kidney, were also evaluated based on standard methods.ResultsThe TTF extract, compound 5, and the reference drug doxorubicin were active in all 9 tested cancer cell lines. The recorded IC50 ranged from 18.32 μM (against B16-F1 murine melanoma cells) to 36.18 μM (against SKMel-505 BRAF wildtype melanoma cells) for TTF, from 10.02 μM (towards MaMel-80a BRAF-V600E homozygous mutant melanoma cells) to 31.73 μM (against SKMel-28 BRAF-V600E homozygous mutant melanoma cells) for compound 5, and from 0.22 μM (against B16-F1 cells) to 9.39 μM (against SKMel-505 cells) for doxorubicin. The study of acute toxicity test showed that the lethal dose (LD50) of this extract was greater than 5000 mg/kg body weight. In the sub-chronic toxicity studies, variations were observed in some biochemical parameters, especially at higher doses.ConclusionTTF and its most active compound (5) are found to be potential cytotoxic agents, meanwhile, TTF was safe when given a single oral dose of 5000 mg/kg. However, caution is necessary in case of prolonged oral administration due to potential alterations of renal function at high doses (> 1000 mg/kg).

Design, Synthesis, and Molecular Modeling Studies of a Novel Benzimidazole as an Aromatase Inhibitor.

In this study, a series of novel 1,3,4-oxadiazole-benzimidazole derivatives were designed and synthesized. Their cytotoxic activities against five cancer cell lines, including A549, MCF-7, C6, HepG2, and HeLa, were evaluated by the MTT assay. The compounds 5b,c showed satisfactory potencies with much higher anticancer activity in comparison to the reference drug doxorubicin against the studied cancer cell lines. In vitro, enzymatic inhibition assays of aromatase (ARO) enzymes were performed. Molecular docking, molecular dynamics simulations, and binding free energy analyses were used to better understand the structure–activity connections and mechanism of action of the aromatase inhibitors. Two types of satisfactory 3D-QSAR (CoMFA and CoMSIA) models were generated, to predict the inhibitory activities of the novel inhibitors. Molecular docking studies were also carried out to find their binding sites and types of their interactions with the aromatase enzyme. Additionally, molecular dynamics simulations were performed to explore the most likely binding modes of compounds 5b,c with CYP19A1.

Synthesis and in vitro Study of Artemisinin/Synthetic Peroxide-Based Hybrid Compounds against SARS-CoV-2 and Cancer.

The newly emerged severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) cause life‐threatening diseases in millions of people worldwide, in particular, in patients with cancer, and there is an urgent need for antiviral agents against this infection. While in vitro activities of artemisinins against SARS‐CoV‐2 and cancer have recently been demonstrated, no study of artemisinin and/or synthetic peroxide‐based hybrid compounds active against both cancer and SARS‐CoV‐2 has been reported yet. However, the hybrid drug's properties (e. g., activity and/or selectivity) can be improved compared to its parent compounds and effective new agents can be obtained by modification/hybridization of existing drugs or bioactive natural products. In this study, a series of new artesunic acid and synthetic peroxide based new hybrids were synthesized and analyzed in vitro for the first time for their inhibitory activity against SARS‐CoV‐2 and leukemia cell lines. Several artesunic acid‐derived hybrids exerted a similar or stronger potency against K562 leukemia cells (81–83 % inhibition values) than the reference drug doxorubicin (78 % inhibition value) and they were also more efficient than their parent compounds artesunic acid (49.2 % inhibition value) and quinoline derivative (5.5 % inhibition value). Interestingly, the same artesunic acid‐quinoline hybrids also show inhibitory activity against SARS‐CoV‐2 in vitro (EC50 13–19 μm) and no cytotoxic effects on Vero E6 cells (CC50 up to 110 μM). These results provide a valuable basis for design of further artemisinin‐derived hybrids to treat both cancer and SARS‐CoV‐2 infections.

Synthesis, Biological Activities and Molecular Docking analysis of a Novel Series of 11H-Indeno[1,2-b]quinoxalin-11-one Derivatives

In this study, olefin adducts were synthesized from Wittig reactions on carbonyl group and stereo-identity of the alkene products. The reaction of 11H-Indeno[1,2-b]quinoxalin-11-one with few stabilized phosphonium ylides yielded a combination of the corresponding E and Z olefins in each case. On the other hand, the reaction of 11H-indeno[1,2-b]quinoxalin-11-one with dialkyl phosphites gave related phosphonates. The aldol condensation reaction of 11H-Indeno[1,2-b]quinoxalin-11-one with boiling dry acetone and/or 2-butanone in presence of aluminum oxide or anhydrous potassium carbonate as a catalyst led to the formation of the β-hydroxy ketones. The nucleophilic addition reaction of acetone and/or 2- butanone to (E)-alkyl 2-(11H-indeno[1,2-b]quinoxalin-11-ylidene)acetate in presence of aluminum oxide or anhydrous potassium carbonate as a catalyst led to the formation of the corresponding an addition products.Reaction mechanisms are taken into consideration and the structural assignments of the new compounds are based on the chemical and spectroscopic evidences. The cytotoxic activity of some new compounds had been evaluated against human hepatocellular carcinoma cell line (HePG2) and human Caucasian breast adenocarcinoma (MCF7). Compounds 6b,c showed higher cytotoxicity towards breast (MCF7) most cancers cellular line than the reference drug (Doxorubicin). The binding mode of phosphonates 6 changed into similarly tested by using molecular docking studies

Anticancer Activity of New Bis-(3-(Thiophen-2-yl)-1H-Pyrazol-4-yl)Chalcones: Synthesis, in-Silico, and in-Vitro Studies

A series of bis-chalcones with alkyl linkers incorporating 3-(thiophen-2-yl)pyrazole 5–10 has been prepared by the condensation reaction of two moles of 3-(thiophen-2-yl)pyrazole-4-aldehyde 4 with one mole of bis- o- or p-(acetophenones) 3a-f. The synthesized compounds 5-10 have been fully characterized and tested as novel anti-cancer agents. The in vitro anticancer activities of the compounds 5-10 were evaluated against a panel of human cancer cell lines (A431, A549, and PC3), and a normal human skin fibroblast BJ1. Compound 10 was the most promising in the prepared series with IC50 (48.7 and 74.2 µg/mL) against epidermoid cancer cell line A431 and the lung adenocarcinoma cell line A549, respectively, compared to the reference drug doxorubicin (IC50, 28.3 and 27.9 µg/mL, respectively). The target compound 10 was investigated theoretically using molecular docking study to different domain sets (1dls, 2c6o, 2w3t, 4kmn, and 4wt2) and they illustrated different modes of action with different binding energies.

Green synthesis of 3-methyl-4-(hetero)aryl methylene isoxazole-5(4H)-ones using WEOFPA/glycerol: evaluation of anticancer and electrochemical behaviour properties.

In the present study, the MCRs of hydroxylamine hydrochloride and ethyl acetoacetate with various substituted aromatic and heteroaromatic aldehydes reacted to produce 3-methyl-4-(hetero)aryl methylene isoxazole-5(4H)-ones derivatives catalyzed by an agro-waste-based solvent medium in an oil bath at 60 °C with stirring. The developed protocol features several advantages, such as being benign and eco-friendly, efficient, avoiding the use of hazardous solvents, and inexpensive, while giving isoxazole derivatives in an 86-92% yield. The homogeneity of the product was confirmed by various spectroscopic analyses. Further, in vitro anticancer evaluation of the synthesized compounds (4h-4o) against lung cancer cells was performed, and among them, 4j, 4k, 4m, and 4o exhibited excellent anticancer activity and compounds 4i and 4n moderate inhibitory activity against lung cancer A549 cells to the reference drug doxorubicin. Furthermore, the derivatives were subjected to electrochemical behaviour studies using cyclic voltammetry and they showed intensive oxidation and reduction potential and also showed excellent anti-oxidant agents. Based on this research study, more and more novel structures of isoxazoles are being designed and synthesized, and their electrochemical behaviour and anticancer activities are studied for the development of novel drug-like candidates.

Anticancer activity of novel 3-(furan-2-yl)pyrazolyl and 3-(thiophen-2-yl)pyrazolyl hybrid chalcones: Synthesis and in vitro studies.

Twelve novel chalcone derivatives were prepared using the Claisen-Schmidt condensation reaction. The reaction of 4-acetyl-5-furan/thiophene-pyrazole derivatives 5 with the corresponding aldehydes 6 afforded the targeted chalcone derivatives 7a-l in good yields. The newly synthesized chalcones were fully characterized by spectrometric and elemental analyses. The in vitro anticancer activities of the novel compounds 7a-l were evaluated against four human cancer cell lines: HepG2 (human hepatocellular carcinoma), MCF7 (human Caucasian breast adenocarcinoma), A549 (lung carcinoma), and BJ1 (normal skin fibroblasts). Compound 7g emerged as the most promising compound, with IC50 = 27.7 µg/ml against A549 cells compared to the reference drug doxorubicin (IC50 = 28.3 µg/ml), and IC50 = 26.6 µg/ml against HepG2 cells compared to the reference drug doxorubicin (IC50 = 21.6 µg/ml). The gene expression and DNA damage values and the DNA fragmentation percentages for compound 7g were determined on the lung and liver cell lines. The expression levels of the AMY2A and FOXG1 genes increased significantly (p < 0.01) in the negative samples of lung cancer cells compared with treated cells. Also, the expression values of the PKM and PSPH genes improved significantly (p < 0.01) in the negative samples compared with treated samples of liver cancer cells. The DNA damage values increased significantly (p < 0.01) in treated lung cell line samples (7g) and the positive control. The results showed a significant decrease (p < 0.05) in DNA damage values in the negative samples of liver cancer cells compared to those treated with 7g. However, the DNA fragmentation values increased significantly (p < 0.01) in the treated lung and liver cell line samples compared with the negative control.

Cytotoxic, apoptotic, and genetic evaluations of Nigella sativa essential oil nanoemulsion against human hepatocellular carcinoma cell lines

BackgroundPhytochemicals and plant extracts are showing promising anticancer potentials. In the current study, the volatile faction (essential oil) of Nigella sativa seeds was evaluated against some hepatocellular carcinoma (HCC). The essential oil was extracted and characterized by chromatographic techniques to reveal its chemical composition, especially thymoquinone. Then, the oil was fabricated in two nanoemulsion formulations (F1 and F2), which differ in their composition of surfactants. The cytotoxicity and apoptotic activities of the essential oil and its nanoemulsions were evaluated in vitro against HepG2 and Huh-7 cell lines. Normal WI-38 cell line was also included in that evaluation to study the selectivity and safety of the different formulations on normal cells.ResultsGas chromatographic analysis indicated that the essential oil is composed mainly of p-cymene (40.0%), thymoquinone (31.2%) and trans-α-thujene (12.8%). Particle size of the nanoemulsions ranged between 9.4 and 119.7 nm depending on the type of surfactant used in the formulation process. The pure essential oil and its two nanoemulsions (F1 and F2) showed dose-dependent antiproliferative activity against both HCC cells. This activity reached its highest cell inhibition in the case of nanoemulsion (F2) where the proliferation percentage was only 21.9% and 9.2% against HepG2 and Huh-7 cells, respectively. The same nanoemulsion (F2) also showed the lowest IC50 values (55.7 and 35.5 µg/ml) against both HepG2 and Huh-7 cells, respectively, compared to 100 µg/ml for the reference drug Doxorubicin. Flow cytometric analysis also confirmed that nanoemulsion (F2) has the highest apoptotic activity compared to nanoemulsion (F1) and the pure unformulated essential oil. Genetic expressions of pro-apoptotic (Bax) and the anti-apoptotic (Bcl-2) gene markers evaluation revealed that nanoemulsion (F2) has better activity in upregulating (Bax) and down-regulate (Bcl-2) with the highest Bax/Bcl-2 ratio (69) was found against Huh-7 cells. All N. sativa nanoemulsions showed minimal cytotoxicity on the normal WI-38 cell, indicating wide safety margins due to selective properties.ConclusionOverall, the study revealed the potentials of N. sativa essential oil, after formulation in specially tailored nanoemulsion for application as potential adjuvant liver anticancer agent.Graphical

Synthesis and Cytotoxic Activity of New Pyrimido[1,2-c]quinazolines, [1,2,4]triazolo[4,3-c]quinazolines and (quinazolin-4-yl)-1H-pyrazoles Hybrids

New hybrid compounds with functionalized quinazoline derivatives and derived tricyclic compounds with varied condensed six and five-membered ring systems were synthesized from simple compounds. The 4-quinazolinimine, 2H-pyrimido[1,2-c] quinazolin-2-one, the pyrido[1,2-c]quinazoline and the [1,2,4]triazolo[4,3-c]quinazoline systems were synthesized starting form the key 4-azido compound and its isosteric analogue; 4-hydrazinyl derivative. Furthermore, a hybrid compound incorporating varied active motifs, the substituted tricyclic structural analog; 3-oxo-2-(quinazolin-4-yl)-2,3-dihydro-1H-pyrazole derivative, in which the pyrazole ring was attached to the quinazoline system via substitution at quinazoline-C4, was also prepared. The synthesized compounds were studied for their cytotoxic activity against the human breast cancer (MCF-7) cell line. The tested compounds possess a high effect against the breast cancer cell line (MCF-7), and compounds 6b, 6e, 8, and 11 showed comparable results to those obtained for the reference drug doxorubicin. The results also showed the effect of substituents in the pyrimidoquinazoline and triazoloquinazoline ring systems on the cytotoxic activity. Additionally, the docking studies revealed that the compounds 6b, 6e, 8, and 11 bound well within the active sites of EGFRWT and EGFRT790M kinases and could be the lead molecules in the discovery of anticancer agents targeting inhibition of EGFRWT and EGFRT790M.

Pharmacophore-linked pyrazolo[3,4-d]pyrimidines as EGFR-TK inhibitors: Synthesis, anticancer evaluation, pharmacokinetics, and in silico mechanistic studies.

Targeting the epidermal growth factor receptors (EGFRs) with small inhibitor molecules has been validated as a potential therapeutic strategy in cancer therapy. Pyrazolo[3,4-d]pyrimidine is a versatile scaffold that has been exploited for developing potential anticancer agents. On the basis of fragment-based drug discovery, considering the essential pharmacophoric features of potent EGFR tyrosine kinase (TK) inhibitors, herein, we report the design and synthesis of new hybrid molecules of the pyrazolo[3,4-d]pyrimidine scaffold linked with diverse pharmacophoric fragments with reported anticancer potential. These fragments include hydrazone, indoline-2-one, phthalimide, thiourea, oxadiazole, pyrazole, and dihydropyrazole. The synthesized molecules were evaluated for their anticancer activity against the human breast cancer cell line, MCF-7. The obtained results revealed comparable antitumor activity with that of the reference drugs doxorubicin and toceranib. Docking studies were performed along with EGFR-TK and ADMET profiling studies. The results of the docking studies showed the ability of the designed compounds to interact with key residues of the EGFR-TK through a number of covalent and noncovalent interactions. The obtained activity of compound 25 (IC50 = 2.89 µM) suggested that it may serve as a lead for further optimization and drug development.

Serjanic Acid Glycosides from Chenopodium hybridum L. with Good Cytotoxicity and Selectivity Profile against Several Panels of Human Cancer Cell Lines.

Two triterpene saponins, including a novel serjanic acid derivative, were isolated from Chenopodium hybridum L. (Amaranthaceae) aerial parts. Their structures were elucidated by a combination of spectroscopic methods (MS, 1D and 2D NMR). Both compounds were evaluated for cytotoxicity and selectivity on skin, prostate, gastrointestinal, thyroid and lung cancer cells. Their effect was dose and time-dependent with varied potency, the highest against prostate PC3 and melanoma WM793, where IC50 was lower than the reference drug doxorubicin. Structure–activity relationship is briefly discussed.