Repurposed organoselenium tethered amidic acids as apoptosis inducers in melanoma cancer via P53, BAX, caspases-3, 6, 8, 9, BCL-2, MMP2, and MMP9 modulations.

Organoselenium (OSe) agents hold promise for preventing cancer due to their potential ability to fight cancer development and protect cells from oxidative damage. Herein, OSe-based maleanilic and succinanilic acids were tested to estimate their antitumor activities against fifteen cancer cell lines. Besides, their potential safety and selectivity were further investigated against two normal cell lines, namely, human skin fibroblasts (HSF) and olfactory ensheathing cell line (OEC) using the growth inhibition percentage (GI%) assay. Moreover, the apoptotic potential of the superior anticancer candidates (8, 9, 10, and 11) was evaluated against P53, BAX, Caspase-3, Caspase-6, Caspase-8, Caspase-9, BCL-2, MMP2, and MMP9 apoptotic markers. Additionally, to enhance our understanding and predict the inhibitory potential of the examined compounds as potential anticancer agents, a thorough structure-activity relationship (SAR) analysis was conducted. On the other hand, molecular docking and ADMET studies were performed for the examined candidates as well. Overall, our findings point to significant anticancer activities of the organoselenium tethered amidic acids, suggesting their promising cytotoxic potential as effective anticancer drugs.

Design and Synthesis of Quinoxaline Hybrids as Modulators of HIF-1a, VEGF, and p21 for Halting Colorectal Cancer.

A library of 16 3-benzyl-N 1-substituted quinoxalin-2-ones was synthesized as N 1-substituted quinoxalines and quinoxaline-triazole hybrids via click reaction. These compounds were tested for their anticancer activity via MTT assay on HCT-116 and normal colonocyte cell lines to assess their cytotoxic potentials and safety profiles. Overall, compounds 6, 9, 14, and 20 were found to be promising anticolorectal cancer agents; they exhibited remarkable cytotoxicity (IC50 0.05-0.07 µM) against HCT-116 cells within their safe doses (EC100) on normal colon cells. Their pronounced anticancer activities were observed as severe morphological alterations and shrinkage of the treated cancer cells. Besides, qRT-PCR analysis was conducted showing the potential of the promising hits to downregulate HIF-1a, VEGF, and BCL-2 as well as their ability to enhance the expression of proapoptotic genes p21, p53, and BAX in HCT-116 cells. In silico prediction revealed that most of our compounds agree with Lipinski and Veber parameters of rules, in addition to remarkable medicinal chemistry and drug-likeness parameters with no CNS side effects. Interestingly, docking studies of the compounds in the VEGFR-2' active site showed significant affinity toward the essential amino acids, which supported the biological results.

Synthesis, DPPH Radical Scavenging, Cytotoxic Activity, and Apoptosis Induction Efficacy of Novel Thiazoles and Bis-thiazoles.

BACKGROUND: Heterocyclic materials-containing thiazoles exhibited incredible importance in pharmaceutical chemistry and drug design due to their extensive biological properties. METHODS: Synthesis of thiazoles and bis-thiazoles from the reaction of 2-((6-Nitrobenzo[ d][1,3]dioxol-5-yl)methylene)hydrazine-1-carbothioamide with hydrazonoyl chlorides in dioxane and in the existence of triethylamine as basic catalyst. The antioxidant, invitro anti-proliferative, and cytotoxicity efficacy of thiazoles and bis-thiazoles were measured. RESULTS: In this work, novel series of 5-methyl-2-(2-(-(6-nitrobenzo[d][1,3]dioxol-5-yl)methylene) hydrazinyl)-4-(aryldiazenyl)thiazoles (4a-f) were prepared via the reaction of hydrazonoyl chlorides 2a-f with 2-((6-nitrobenzo[d][1,3]dioxol-5-yl)methylene)hydrazine-1-carbothioamide (1) in dioxane and employing triethylamine as basic catalyst. Following the same procedure, bisthiazoles (6, 8, and 10) have been synthesized by utilizing bis-hydrazonoyl chlorides (5, 7, and 9) and carbothioamide 1 in a molar ratio (1:2), respectively. The distinctive features in the structure of isolated products were elucidated by spectroscopic tools and elemental analyses. The antioxidant, invitro anti-proliferative, cytotoxicity, and anti-cancer efficacy of thiazoles and bis-thiazoles were evaluated. Compounds 4d and 4f were the most potent antioxidant agents. Gene expression of apoptosis markers and fragmentation assay of DNA were assessed to explore the biochemical mechanism of synthesized products. Thiazoles significantly inhibited cell growth and proliferation more than bis-thiazoles. They induced apoptosis through induction of apoptotic gene expression P53 and downregulation of antiapoptotic gene expression Bcl-2. Moreover, they induced fragmentation of DNA in cancer cells, indicating that they could be employed as anticancer agents by inhibiting tumor growth and progression and can be considered effective compounds in the strategy of anti-cancer agents' discovery. CONCLUSION: Synthesis, DPPH Radical Scavenging, Cytotoxic activity, and Apoptosis Induction Efficacy based on Novel Thiazoles and Bis-thiazoles.

A Comprehensive Pan-Cancer Analysis Identifies CEP55 as a Potential Oncogene and Novel Therapeutic Target.

Emerging research findings have shown that a centrosomal protein (CEP55) is a potential oncogene in numerous human malignancies. Nevertheless, no pan-cancer analysis has been conducted to investigate the various aspects and behavior of this oncogene in different human cancerous tissues. Numerous databases were investigated to conduct a detailed analysis of CEP55. Initially, we evaluated the expression of CEP55 in several types of cancers and attempted to find the correlation between that and the stage of the examined malignancies. Then, we conducted a survival analysis to determine the relationship between CEP55 overexpression in malignancies and the patient's survival. Furthermore, we examined the genetic alteration forms and the methylation status of this oncogene. Additionally, the interference of CEP55 expression with immune cell infiltration, the response to various chemotherapeutic agents, and the putative molecular mechanism of CEP55 in tumorigenesis were investigated. The current study found that CEP55 was upregulated in cancerous tissues versus normal controls where this upregulation was correlated with a poor prognosis in multiple forms of human cancers. Additionally, it influenced the level of different immune cell infiltration and several chemokines levels in the tumor microenvironment in addition to the response to several antitumor drugs. Herein, we provide an in-depth understanding of the oncogenic activities of CEP55, identifying it as a possible predictive marker as well as a specific target for developing anticancer therapies.

Integration of Chemoinformatics and Multi-Omics Analysis Defines ECT2 as a Potential Target for Cancer Drug Therapy.

Epithelial cell transforming 2 (ECT2) is a potential oncogene and a number of recent studies have correlated it with the progression of several human cancers. Despite this elevated attention for ECT2 in oncology-related reports, there is no collective study to combine and integrate the expression and oncogenic behavior of ECT2 in a panel of human cancers. The current study started with a differential expression analysis of ECT2 in cancerous versus normal tissue. Following that, the study asked for the correlation between ECT2 upregulation and tumor stage, grade, and metastasis, along with its effect on patient survival. Moreover, the methylation and phosphorylation status of ECT2 in tumor versus normal tissue was assessed, in addition to the investigation of the ECT2 effect on the immune cell infiltration in the tumor microenvironment. The current study revealed that ECT2 was upregulated as mRNA and protein levels in a list of human tumors, a feature that allowed for the increased filtration of myeloid-derived suppressor cells (MDSC) and decreased the level of natural killer T (NKT) cells, which ultimately led to a poor prognosis survival. Lastly, we screened for several drugs that could inhibit ECT2 and act as antitumor agents. Collectively, this study nominated ECT2 as a prognostic and immunological biomarker, with reported inhibitors that represent potential antitumor drugs.

Capric Acid Behaves Agonistic Effect on Calcitriol to Control Inflammatory Mediators in Colon Cancer Cells.

Inflammation prompts cancer development and promotes all stages of tumorigenesis. Calcitriol is a nutraceutical essential regulator for host health benefits. However, the influence of calcitriol on inflammatory mediators involved in cancer cells is not clear. This study aimed to assess the sensitivity of calcitriol alone and combined with capric acid, and identify the possible influence of calcitriol on inflammatory mediators. The colorectal cancer cell line (HCT116) was induced by LPS/TNF-α and the inflammation and metastatic mediators (IL-1ß, IL-6, IL-17) were quantified in calcitriol and capric acid supplemented colon cancer cells. The mRNA and protein expression of MMP-2, NF-κB and COX-2 were quantified. The significant reduction in MMP-2 expression was confirmed at combination treatment by zymogram analysis. Our findings demonstrated the anti-inflammatory and anti-metastatic potentials of capric acid and calcitriol in individual exposure in a combination of human colon cancer cell lines (HCT116). These abilities may be due to the inhibition of COX-2 mediators and NF-κB transcription factor and reciprocally regulated MMP-2 and MMP-9 signaling pathways. These findings elucidate the activation of COX-2 and NF-κB via disruption of the cellular outer matrix could be considered a novel molecular target suitable for colorectal cancer therapy. This study confirmed that capric acid activates calcitriol sensitization in colon cancer cells and could be used as a successful supplement for intestinal diseases and colon aberrations.

Carboxymethyl Cellulose/Zn-Organic Framework Down-Regulates Proliferation and Up-Regulates Apoptosis and DNA Damage in Colon and Lung Cancer Cell Lines.

A solvothermal technique was used to prepare a Zn-benzenetricarboxylic acid (Zn@BTC) organic framework covered with a carboxymethyl cellulose (CMC/Zn@BTC). Fourier transform infrared spectroscopy (FTIR), field emission scanning electron microscope (FESEM), and Brunauer, Emmett, and Teller (BET) surface area were applied to characterize CMC/Zn@BTC. Moreover, the anticancer, anti-migrative, anti-invasive, and anti-proliferative action of CMC/Zn@BTC nanoparticles were assessed on cancer cell lines. Apoptotic markers and DNA damage were assessed to explore the cellular and biological changes induced by CMC/Zn@BTC nanoparticles. The microscopic observation revealed that CMC controls the surface morphology and surface characteristics of the Zn@BTC. The obtained BET data revealed that the Zn@BTC nanocomposite surface area lowers from 1061 m2/g to 740 m2/g, and the pore volume decreases from 0.50 cm3/g to 0.37 cm3/g when CMC is applied to Zn@BTC nanocomposites. The cellular growth of DLD1 and A549 was suppressed by CMC/Zn@BTC, with IC50 values of 19.1 and 23.1 µg/mL, respectively. P53 expression was upregulated, and Bcl-2 expression was downregulated by CMC/Zn@BTC, which promoted the apoptotic process. Furthermore, CMC/Zn@BTC caused DNA damage in both cancer cell lines with diverse impact, 66 percent (A549) and 20 percent (DLD1) compared to cisplatin's 52 percent reduction. CMC/Zn@BTC has anti-invasive properties and significantly reduced cellular migration. Moreover, CMC/Zn@BTC aims key proteins associated with metastasis, proliferation and programmed cellular death.

Chitosan Containing Nano Zn-Organic Framework: Synthesis, Characterization and Biological Activity.

A biologically active agent based on a Zn-1,3,5-benzen tricarboxylic acid (Zn-BTC) framework incorporated into a chitosan (CS) biopolymer (Zn-BTC@CS) was successfully synthesized using a microwave irradiation technique. The synthesized Zn-BTC@CS was characterized using a scanning electron microscope (SEM) and the obtained data indicated a highly smooth surface morphology of the synthesized Zn-BTC and no morphological changes when the Zn-BTC covered the CS. In addition, the particle size diameter varied from 20 to 40 nm. XRD displayed a well-maintained Zn-BTC structure, and the crystal structure of Zn-BTC was not distorted by the composition of Zn-BTC and chitosan in the nanocomposite. Data from BET analysis revealed that the specific surface area of the Zn-BTC was reduced from 995.15 m2/g to 15.16 m2/g after coating with chitosan. The pore size distribution and pore volume of the Zn-BTC, Zn-BTC@CS were centered at 37.26 nm and at 22.5 nm, respectively. Zn-BTC@CS exhibited anticancer efficacy against lung and colon cancer cell lines. Zn-BTC@CS inhibited the proliferation of A549 and DLD-1 cancer cell lines in a dose-dependent manner with IC50 values of 13.2 and 19.8 µg/mL for the colon and lung cancer cell lines, respectively. Zn-BTC@CS stimulated the apoptotic process through up-regulating P53 expression and down-regulating Bcl-2 expression. Moreover, Zn-BTC@CS induced in vitro DNA fragmentation in both cancer cell lines with significantly different affinity by 66% (A549) and 20% (DLD-1) versus 52% reduction by Cisplatin. Zn-BTC@CS (IC50) exhibited anti-invasive activity and dramatically inhibited the migration of lung and colon cancer cell lines. This study provides evidence that Zn-BTC@CS targets the essential proteins involved in proliferation, metastasis, and apoptosis. Thus, Zn-BTC@CS has chemotherapeutic potential for inhibiting lung and colon cancer viability and growth.

Baicalein and Αlpha-Tocopherol Inhibit Toll-like Receptor Pathways in Cisplatin-Induced Nephrotoxicity.

Cisplatin (CP) is a conventional chemotherapeutic agent with serious adverse effects. Its toxicity was linked to the stimulation of oxidative stress and inflammation. As a result, this study explored the protective effect of baicalein and alpha-tocopherol in nephrotoxicity induced by cisplatin. Until receiving an intraperitoneal injection of CP (3 mg/kg BW), rats were given baicalein orally 100 mg/kg for seven days or/and a single intraperitoneal injection of α-tocopherol 250 mg/kg. Renal function was tested to explore whether baicalein and α-tocopherol have any beneficial effects; blood urea nitrogen (BUN), serum creatinine, malondialdehyde (MDA) content, antioxidant activity biomarkers and histopathology of renal tissue, oxidative stress biomarkers, inflammatory response markers, and histopathological features of kidney architecture were measured. Cisplatin treatment resulted in extreme renal failure, as measured by high serum creatinine and BUN levels and severe renal changes. Cisplatin therapy resulted in increased lipid peroxidation and decreased glutathione and superoxide dismutase levels, reflecting oxidative stress. Upon treatment with α-tocopherol, baicalein, and combined therapy, there was augmentation in the antioxidant status as well as a reduction in IL-6, NF-κB, TNF, TLR2, and TLR4 and a significant increase in Keap-1 and NRF-2. The combined treatment was the most effective and the nearest to the normal status. These findings suggest that baicalein and α-tocopherol may be useful in preventing cisplatin-induced nephrotoxicity.

Growth Optimization and Secondary Metabolites Evaluation of Anabaena variabilis for Acetylcholinesterase Inhibition Activity.

Cyanobacteria comprise a good natural resource of a potential variety of neuro-chemicals, including acetylcholinesterase inhibitors essential for Alzheimer's disease treatment. Accordingly, eight different cyanobacterial species were isolated, identified, and evaluated on their growth on different standard nutrient media. It was found that the modified Navicula medium supported the highest growth of the test cyanobacteria. The effects of methylene chloride/methanol crude extracts of the test cyanobacteria on acetylcholinesterase activity were examined and compared. Anabaena variabilis (KU696637.1) crude extract recorded the highest acetylcholinesterase inhibition (62 ± 1.3%). Navicula medium chemical components were optimized through a Plackett-Burman factorial design. The biomass of Anabaena variabilis increased significantly when grown on the optimized medium compared to that of control. The chemical analysis of the fractions derived from Anabaena variabilis showed the presence of two compounds in significant amounts: the flavonoid 5,7-dihydroxy-2-phenyl-4H-chrome-4-one and the alkaloid 4-phenyl-2-(pyridin-3-yl) quinazoline. Molecular docking studies revealed that both compounds interact with the allosteric binding site of acetylcholinesterase at the periphery with π-π stackings with Tyr341 and Trp286 with good, predicted partition coefficient. The compounds obtained from this study open the door for promising drug candidates to treat Alzheimer's disease for their better pharmacodynamics and pharmacokinetic properties.

Development of superior antibodies against the S-protein of SARS-Cov-2 using macrocyclic epitopes.

One of the proven methods to prevent and inhibit viral infections is to use antibodies to block the initial Receptor Binding Domain (RBD) of SARS-CoV-2 S protein and avoid its binding with the host cells. Thus, developing these RBD-targeting antibodies would be a promising approach for treating the SARS-CoV-2 infectious disease and stop virus replication. Macrocyclic epitopes constitute closer mimics of the receptor's actual topology and, as such, are expected to be superior epitopes for antibody generation. This work demonstrated the vital effect of the three-dimensional shape of epitopes on the developed antibodies' activity against RBD protein of SARS-CoV-2. The molecular dynamics studies showed the greater stability of the cyclic epitopes in comparison with the linear counterpart, which was reflected in the activity of their produced antibodies. Indeed, the antibodies we developed using macrocyclic epitopes showed superiority with respect to binding to RBD proteins compared to antibodies formed from a linear peptide. The results of the present work constitute a roadmap for developing superior antibodies that could be used to inhibit the activity of the SARS-CoV-2 and prevent its reproduction.

Structure-Based Epitope Design: Toward a Greater Antibody-SARS-CoV-2 RBD Affinity.

Efficient COVID-19 vaccines are widely acknowledged as the best way to end the global pandemic. SARS-CoV-2 receptor-binding domain (RBD) plays fundamental roles related to cell infection. Antibodies could be developed to target RBD and represent a potential approach for the neutralization of the virus. Epitopes used to produce antibodies are generally linear peptides and thus possess multiple confirmations that do not reflect the actual topology of the targeted part in the native protein. On the other hand, macrocyclic epitopes could constitute closer mimics of the native protein topology and, as such, could generate superior antibodies. In this study, we demonstrated the vital effect of the size and the three-dimensional shape of epitopes on the activity of the developed antibodies against the RBD of SARS-CoV-2. The molecular dynamics studies showed the greater stability of the cyclic epitopes compared with the linear counterparts, which was reflected in the affinity of the produced antibodies. The antibodies developed using macrocyclic epitopes showed superiority with respect to binding to RBD compared to antibodies formed from linear peptides. This study constitutes a roadmap for developing superior antibodies that could be used to inhibit the activity of SARS-CoV-2.

Oleanolic Acid Suppressed DMBA-Induced Liver Carcinogenesis through Induction of Mitochondrial-Mediated Apoptosis and Autophagy.

Phytochemicals appeared as a rich source of efficient and safe agents against many diseases like cancer. Various herbal sources are rich in oleanolic acid (OA). The scope of this study was to assess the biochemical and molecular mechanisms implicated in the ameliorative potency of OA against DMBA-induced liver carcinogenesis. Forty-eight male albino mice were assigned randomly to five groups (eight mice each) as follows: control healthy group, olive oil group, OA group, DMBA group, and DMBA with OA. Apoptosis, autophagy, inflammation, proliferation, and angiogenesis were investigated in the tissue samples. Histopathological examination was carried out as well as liver enzymes activity and other hepatic antioxidant and inflammatory biomarkers. The treatment with OA effectively suppressed the DMBA-initiated liver carcinogenesis via modulation of antioxidant status, induction of apoptosis and autophagy through modulating the expression of Caspase-3, Bcl-2 and Beclin-1, inhibiting angiogenesis (VEGF), proliferation (PCNA), and improved liver function and histological picture with a reduction in AFP level. Additionally, OA applies its antitumor effects by inhibition of proinflammatory transcription factor NF-κB and inflammatory markers (TNF-α and Cox-2) associated with DMBA administration. The present study shows that OA treatment efficiently suppressed the DMBA-initiated liver carcinogenesis through induction of mitochondrial-mediated apoptosis and autophagy and modulating inflammation.

Prunus Armeniaca L. Seed Extract and Its Amygdalin Containing Fraction Induced Mitochondrial-Mediated Apoptosis and Autophagy in Liver Carcinogenesis.

BACKGROUND: Despite significant advances in therapeutic interventions, liver cancer is the leading cause of cancer mortality in the world. Potential phytochemicals have shown to be promising agents against many life-threatening diseases because of their low toxicity and potential effectiveness. OBJECTIVE: The current study aims to conduct an in vitro investigation of the anticancer activity of Apricot Extract (AE) and Amygdalin Containing Fraction (ACF), additionally studying their therapeutic effects on DMBAinduced liver carcinogenesis mice model to highlight their related biochemical and molecular mechanisms. METHODS AND RESULTS: Amygdalin was isolated from the seeds of P. armeniaca L. Male mice received AE or ACF, DMBA, DMBA+AE, DMBA+ACF, and vehicles. The oxidative stress and antioxidant markers, cell proliferation by flow cytometric analysis of Proliferating Cell Nuclear Antigen (PCNA) expression, angiogenesis marker (VEGF), inflammatory marker (TNF-α), apoptotic, anti-apoptotic and autophagy genes expression (caspase-3, Bcl-2, and Beclin-1) were investigated. AE and ACF were found to stimulate the apoptotic process by up-regulating caspase-3 expression and down-regulating Bcl-2 expression. They also reduced VEGF and PCNA levels and increased the antioxidant defense system. Moreover, AE and ACF treatments also inhibited HepG2 and EAC cell proliferation and up-regulated Beclin-1 expression. CONCLUSION: This study provides evidence that, in DMBA-induced hepatocarcinogenesis, the key proteins involved in the proliferation, angiogenesis, autophagy, and apoptosis are feasible molecular targets for hepatotherapeutic potential using AE and ACF.

Zinc oxide nanoparticles augment CD4, CD8, and GLUT-4 expression and restrict inflammation response in streptozotocin-induced diabetic rats.

This study evaluated the biochemical, molecular, and histopathological mechanisms involved in the hypoglycaemic effect of zinc oxide nanoparticles (ZnONPs) in experimental diabetic rats. ZnONPs were prepared by the sol-gel method and characterised by scanning and transmission electron microscopy (SEM and TEM). To explore the possible hypoglycaemic and antioxidant effect of ZnONPs, rats were grouped as follows: control group, ZnONPs treated group, diabetic group, and diabetic + ZnONPs group. Upon treatment with ZnONPs, a significant alteration in the activities of superoxide dismutase, glutathione peroxidase, and the levels of insulin, haemoglobin A1c, and the expression of cluster of differentiation 4+ (CD4+), CD8+ T cells, glucose transporter type-4 (GLUT-4), tumour necrosis factor, and interleukin-6 when compared to diabetic and their control rats. ZnONPs administration to the diabetic group showed eminent blood glucose control and restoration of the biochemical profile. This raises their active role in controlling pancreas functions to improve glycaemic status as well as the inflammatory responses. Histopathological investigations showed the non-toxic and therapeutic effect of ZnONPs on the pancreas. TEM of pancreatic tissues displayed restoration of islets of Langerhans and increased insulin-secreting granules. This shows the therapeutic application of ZnONPs as a safe anti-diabetic agent and to have a potential for the control of diabetes.

Prognostic value of vascular endothelial growth factor in both conventional and drug eluting beads transarterial chemoembolization for treatment of unresectable hepatocellular carcinoma in HCV patients.

OBJECTIVES: This work aimed to measure serum vascular endothelial growth factor (VEGF) levels before and after Conventional transarterial chemoembolization (cTACE) versus drug-eluting beads (DEB)-TACE and evaluate its efficacy in predicting response to therapy and tumor recurrence. METHODS: 114 patients with unresectable hepatocellular carcinoma complicating hepatitis C virus-related cirrhosis were included. They underwent cTACE (58) or DEB-TACE (56). VEGF serum levels were measured before and on days 1 and 30 after TACE. Patients with complete response (CR) after TACE were followed-up for one year. Statistical analysis was done. RESULTS: VEGF level was higher than baseline after cTACE (P < 0.001), and DEB-TACE (P = 0.004). It was also significantly higher in patients with progressive disease (P < 0.001). VEGF level at cut off values of 97.3, 149.8, and 104.1 pg/ml could discriminate disease progression from treatment success with area under ROC curves of 0.806, 0.775, and 0.771, respectively. The sensitivity was 88.9%, 88.9%, and 77.8% and specificity was 62.5%, 64.6 and 66.7%, respectively. However, no relation to tumor recurrence in CR group could be detected after one year. CONCLUSION: VEGF serum levels may predict response to therapy in patients treated by DEB-TACE or cTACE but it has no relation to tumor recurrence.

Synthesis and biochemical studies of novel organic selenides with increased selectivity for hepatocellular carcinoma and breast adenocarcinoma.

Nineteen organoselenides were synthesized and tested for their intrinsic cytotoxicity in hepatocellular carcinoma (HepG2) and breast adenocarcinoma (MCF-7) cell lines and their corresponding selective cytotoxicity (SI) was estimated using normal lung fibroblast (WI-38) cells. Most of the organic selenides exhibited good anticancer activity, and this was more pronounced in HepG2 cells. Interestingly, the naphthoquinone- (5), thiazol- (12), and the azo-based (13) organic selenides demonstrated promising SI (up to 76). Furthermore, the amine 4c, naphthoquinone 5, and azo-based 13 and 15 organic selenides were able to down-regulate the expression of Bcl-2 and up-regulate the expression levels of IL-2, IL-6 and CD40 in HepG2 cells compared to untreated cells. Moreover, most of the synthesized candidates manifested good free radical-scavenging and GPx-like activities comparable to vitamin C and ebselen. The obtained results suggested that some of the presented organoselenium candidates have promising anti-HepG2 and antioxidant activities.

Anticancer activity, dual prooxidant/antioxidant effect and apoptosis induction profile of new bichalcophene-5-carboxamidines.

A series of thirteen new aryl/hetarylbichalcophene-5-carboxamidines was prepared and screened for an in vitro anti-proliferative activity against sixty cancer cell lines. The tested monocationic bichalcophenes displayed promising potent anticancer activity against most cancer cell lines with GI50 values of 1.34-3.09 µM. The most potent compound was derivative 8 (median GI50 and TGI values of 1.34 and 3.23 µM, respectively), being also the least cytotoxic in this bichalcophene series with an LC50 of 77.6 µM. The most responsive cancer cell lines were leukemia (SR and K-562) and colon (HCT-15 and HT29) with GI50 in the sub-micromolar range. The effect of the tested bichalcophenes on normal human lung fibroblast (WI-38) cell line showed that they exerted their antiproliferative activity outside the realms of causing any toxicity in normal cells. To study apoptotic profiles of representatives of this class, compounds 4h, 4i, and 8 were found to cause significant reductions in cdk1 expression in HCT-116 colon cells by 46, 79, and 84%, respectively versus 52% reduction by 5- Flourouracil (5-FU). These three compounds were also unique being the only derivatives that significantly elevated the expression of p53 by ∼2, 4, and 5 folds, respectively. The tested bichalcophenes exhibited moderate to potent antioxidant activity in DPPH and ABTS as well as hydroxyl radical scavenging assays. Moreover, compounds IIIb, IIIc, 4c, and 4i, showed the highest pro-oxidant activity. Finally, to aid future endeavors for optimization of this series, a 5 descriptor 2D-QSAR model was derived from the common physicochemical parameters of these bichalcophenes and the external validation proved the model's good predictive efficiency.

Cytoprotective and antioxidant properties of organic selenides for the myelin-forming cells, oligodendrocytes.

Here a new series of twenty-one organoselenides, of potential protective activity, were synthesized and tested for their intrinsic cytotoxicity, anti-apoptotic and antioxidant capacities in oligodendrocytes. Most of the organoselenides were able to decrease the ROS levels, revealing antioxidant properties. Compounds 5b and 7b showed a high glutathione peroxidase (GPx)-like activities, which were 1.5 folds more active than ebselen. Remarkably, compound 5a diminished the formation of the oligodendrocytes SubG1 peak in a concentration-dependent manner, indicating its anti-apoptotic properties. Furthermore, based on the SwissADME web interface, we performed an in-silico structure-activity relationship to explore the drug-likeness of these organoselenides, predicting the pharmacokinetic parameters for compounds of interest that could cross the blood-brain barrier. Collectively, we present new organoselenide compounds with cytoprotective and antioxidant properties that can be considered as promising drug candidates for myelin diseases.

Sucrose diester of aryldihydronaphthalene-type lignans from Echium angustifolium Mill. and their antitumor activity.

Four previously undescribed sucrose diester of aryldihydronaphthalene-type lignans, named echiumins A-D, were isolated from the butanol fraction of Echium angustifolium Mill, in addition to a known compound, trigonotin A, which is reported for the first time from the title plant. The structures of isolated compounds were elucidated using spectroscopic methods such as HRESIMS and 1D and 2D NMR spectroscopy. The isolated compounds displayed strong to weak antitumor activity against HepG2 and MCF7 cancer cell lines, with echiumins A and D showed the most potent activity.