Selenium-containing Molecules Research Articles

Structure of the Se4 Isomers─An Ab Initio Study.

This study investigates the equilibrium geometries of four different Se4 isomers using the coupled cluster single and double perturbative (CCSD(T)) method, extrapolating to the complete basis sets. The ground-state geometry of the Se4 isomer with the C2v structure (2.8715 Å, 2.1750 Å, and 88.4°) is found to be very close to other theoretical values (2.910 Å, 2.224 Å, and 90.0°) for the Se═Se and Se-Se bond lengths and valence angle. Additionally, the adiabatic electron affinity, vertical electron affinity, and vertical ionization energy are calculated. The multireference configuration interaction method was used to calculate transitions from the singlet ground state to some excited counterparts, including the vertical excitation energy, oscillator strength, and main electronic configuration. The predicted wavelengths of electronic transitions to 11Bu, 11Au with C2h symmetry, and 11B1 state with the C2V symmetry could match the experimental NIR absorption band at 710-850 nm. These transitions and electronic properties may provide insights into the role of selenium in astrophysical environments, where 74Se in the solar system has been confirmed to originate from the supernova explosion process. The theoretical results offer a deeper understanding of Se4 electronic and geometric structures while also providing crucial spectroscopic data that could aid in the identification of selenium-containing molecules in extraterrestrial environments.

The Chemistry of Selenosilanes: A Topic Overview.

Selenium-containing molecules represent a valuable class of compounds with a variety of applications in chemical and biological fields. Selenated reagents are used as intermediates to introduce functional groups (e.g., double bonds) onto different substrates or in the synthesis of various selenated derivatives. Among the variety of selenium-containing reagents, silyl selenides are frequently used to transfer a selenated moiety due to the smooth functionalization of the Se-Si bond, which allows for the generation of selenium nucleophilic species under mild conditions. While the use of the analogous sulfur nucleophiles, namely silyl sulfides, has been widely explored, a relatively limited number of reports on selenosilanes have been provided. This contribution will focus on the application of selenosilanes as nucleophiles in a variety of organic transformations, as well as under radical and redox conditions. The use of silyl selenides to prepare metal complexes and as selenium precursors of materials for atomic layer deposition will also be discussed.

Recent Advances in the Synthesis and Antioxidant Activity of Low Molecular Mass Organoselenium Molecules.

Selenium is an essential trace element in living organisms, and is present in selenoenzymes with antioxidant activity, like glutathione peroxidase (GPx) and thioredoxin reductase (TrxR). The search for small selenium-containing molecules that mimic selenoenzymes is a strong field of research in organic and medicinal chemistry. In this review, we review the synthesis and bioassays of new and known organoselenium compounds with antioxidant activity, covering the last five years. A detailed description of the synthetic procedures and the performed in vitro and in vivo bioassays is presented, highlighting the most active compounds in each series.

In silico evidences of Mpro inhibition by a series of organochalcogen-AZT derivatives and their safety in Caenorhabditis elegans

BackgroundThe new coronavirus (SARS-CoV-2) pandemic emerged in 2019 causing millions of deaths. Vaccines were quickly developed and made available in 2021. Despite the availability of vaccines, some subjects refuse to take the immunizing or present comorbities, therefore developing serious cases of COVID-19, which makes necessary the development of antiviral drugs. Previous studies have demonstrated that ebselen, a selenium-containing molecule, can inhibit SARS-CoV-2 Mpro. In addition, selenium is a trace element that has antiviral and anti-inflammatory properties. Zidovudine (AZT) has been widely used against HIV infections and its action against SARS-CoV-2 may be altered by the structural modification with organochalcogen moieties, but this hypothesis still needs to be tested. MethodsIn the present work we evaluated the Mpro inhibition capacity (in silico), the safety and antioxidant effect of six organochalcogen AZT-derivatives using the free-living nematode Caenorhabditis elegans, through acute (30 min) and chronic (48) exposure protocols. ResultsWe observed that the molecules were safe at a concentration range of 1–500 µM and did not alter any toxicological endpoint evaluated. Furthermore, the molecules are capable to decrease the ROS formation stimulated by hydrogen peroxide, to modulate the expression of important antioxidant enzymes such superoxide-dismutase-3 and glutathione S-transferese-4 and to stimulate the translocation of the DAF-16 to the cell nucleus. In addition, the molecules did not deplete thiol groups, which reinforces their safety and contribution to oxidative stress resistance. ConclusionsWe have found that compounds S116l (a Tellurium AZT-derivative) and S116h (a Selenium-AZT derivative) presented more promising effects both in silico and in vivo, being strong candidates for further in vivo studies.

Druggable Biomarkers Altered in Clear Cell Renal Cell Carcinoma: Strategy for the Development of Mechanism-Based Combination Therapy.

Targeted therapeutics made significant advances in the treatment of patients with advanced clear cell renal cell carcinoma (ccRCC). Resistance and serious adverse events associated with standard therapy of patients with advanced ccRCC highlight the need to identify alternative 'druggable' targets to those currently under clinical development. Although the Von Hippel-Lindau (VHL) and Polybromo1 (PBRM1) tumor-suppressor genes are the two most frequently mutated genes and represent the hallmark of the ccRCC phenotype, stable expression of hypoxia-inducible factor-1α/2α (HIFs), microRNAs-210 and -155 (miRS), transforming growth factor-beta (TGF-ß), nuclear factor erythroid 2-related factor 2 (Nrf2), and thymidine phosphorylase (TP) are targets overexpressed in the majority of ccRCC tumors. Collectively, these altered biomarkers are highly interactive and are considered master regulators of processes implicated in increased tumor angiogenesis, metastasis, drug resistance, and immune evasion. In recognition of the therapeutic potential of the indicated biomarkers, considerable efforts are underway to develop therapeutically effective and selective inhibitors of individual targets. It was demonstrated that HIFS, miRS, Nrf2, and TGF-ß are targeted by a defined dose and schedule of a specific type of selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocystein (MSC). Collectively, the demonstrated pleiotropic effects of selenium were associated with the normalization of tumor vasculature, and enhanced drug delivery and distribution to tumor tissue, resulting in enhanced efficacy of multiple chemotherapeutic drugs and biologically targeted molecules. Higher selenium doses than those used in clinical prevention trials inhibit multiple targets altered in ccRCC tumors, which could offer the potential for the development of a new and novel therapeutic modality for cancer patients with similar selenium target expression. Better understanding of the underlying mechanisms of selenium modulation of specific targets altered in ccRCC could potentially have a significant impact on the development of a more efficacious and selective mechanism-based combination for the treatment of patients with cancer.

Isotopologue pattern based data mining for selenium species from HILIC-ESI-Orbitrap-MS-derived spectra.

Automated and specific picking of selenium-containing molecular entities has not been an obvious option for software tools associated with electrospray high-resolution mass spectrometry (MS). In our study, a comprehensive pattern matching approach based on intra-isotopologue distance and isotopologue ratio data was critically evaluated in terms of reproducibility and selenium isotope selection on three samples, including selenized Torula yeast and the selenium hyperaccumulator plant Cardamine violifolia. Hydrophilic interaction liquid chromatography was applied to provide a one-step separation for water soluble metabolites to put an end to the need for either orthogonal setups or poor retention on reversed phase chromatography. Assistance from inductively coupled plasma-MS was taken only for chromatographic verification purposes, and the involvement of absolute mass defect (MD) data in selenometabolite-specific screening was assessed by multivariate statistical tools. High focus was placed on screening efficiency and on the validation of discovered selenized molecules to avoid reporting of artefacts. From the >1000 molecular entries detected, selenium-containing molecules were picked up with a recovery rate of >88% and a false positive rate of <10%. Isotop(ologu)e pairs of 78Se-80Se and 80Se-82Se proved to be the most performant in the detection. On the basis of accurate mass information and hypothetical deamination processes, elemental composition could be proposed for 72 species out of the 75 selenium species encountered without taking into account selenocompound databases. Absolute MD data were used to significantly differentiate a potentially sample-specific subgroup of false positive molecular entities from non-selenized and selenized entities.

MicroRNA Expression in Clear Cell Renal Cell Carcinoma Cell Lines and Tumor Biopsies: Potential Therapeutic Targets.

This study was carried out to quantitate the expression levels of microRNA-17, -19a, -34a, -155, and -210 (miRs) expressed in nine clear cell renal cell carcinoma (ccRCC) and one chromophobe renal cell carcinoma cell line with and without sarcomatoid differentiation, and in six primary kidney tumors with matching normal kidney tissues. The data in the five non-sarcomatoid ccRCC cell lines—RC2, CAKI-1, 786-0, RCC4, and RCC4/VHL—and in the four ccRCC with sarcomatoid differentiation—RCJ41T1, RCJ41T2, RCJ41M, and UOK-127—indicated that miR-17 and -19a were expressed at lower levels relative to miR-34a, -155, and -210. Compared with RPTEC normal epithelial cells, miR-34a, miR-155, and miR-210 were expressed at higher levels, independent of the sarcomatoid differentiation status and hypoxia-inducible factors 1α and 2α (HIFs) isoform expression. In the one chromophobe renal cell carcinoma cell line, namely, UOK-276 with sarcomatoid differentiation, and expressing tumor suppressor gene TP53, miR-34a, which is a tumor suppressor gene, was expressed at higher levels than miR-210, -155, -17, and -19a. The pilot results generated in six tumor biopsies with matching normal kidney tissues indicated that while the expression of miR-17 and -19a were similar to the normal tissue expression profile, miR-210, -155, -and 34a were expressed at a higher level. To confirm that differences in the expression levels of the five miRs in the six tumor biopsies were statistically significant, the acquisition of a larger sample size is required. Data previously generated in ccRCC cell lines demonstrating that miR-210, miR-155, and HIFs are druggable targets using a defined dose and schedule of selenium-containing molecules support the concept that simultaneous and concurrent downregulation of miR-210, miR-155, and HIFs, which regulate target genes associated with increased tumor angiogenesis and drug resistance, may offer the potential for the development of a novel mechanism-based strategy for the treatment of patients with advanced ccRCC.

Prospects for the use of synthetic organoselenium compounds for the correction of metabolic and immune status during vaccination with live attenuated vaccines against especially dangerous infections

This review article analyzes the data on the role of selenium in the regulation of the metabolic and immune status of a macroorganism. The data on endogenous functional selenium-containing molecules, which include selenocysteine, selenomethionine, and selenoproteins, are considered. The data on the pathologies associated with the deficiency of this microelement, its immunotropic properties and adjuvant effects are presented. The role of selenoproteins in the regulation of redox processes has been shown. The data on the immunotropic activity of compounds containing selenium and the prospects for their use as adjuvants are analyzed. The last section is devoted to the analysis of literature data on the biological properties of synthetic selenium compounds with an activity that mimics the catalytic activity of selenoproteins. The analysis of the data on the functional activity of selenoproteins carried out in this work indicates their key role in the regulation of metabolic and immune processes, as well as in maintaining homeostasis. The information presented in this review on the biological activity and mechanisms of action of new synthetic low-toxic organic compounds of selenium can serve as a basis for the development of nonspecific means of metabolic and immune correction of vaccinal processes caused by both live attenuated vaccines and artificially created ones.

Effects of selenium-enriched prebiotic on the growth performance, innate immune response, oxidative enzyme activity and microbiome of rainbow trout (Oncorhynchus mykiss)

Using prebiotics as functional ingredients in aquafeed is an emerging approach to prevent disease and improve fish production. This study explored the effect of supplementing aquafeed with selenium-enriched prebiotic on the growth performance, plasma lysozyme activity, and oxidative enzymes activities of various tissues of the rainbow trout, Oncorhynchus mykiss. The fish scale and intestinal microbiomes were also characterized. A genetically- modified, whole-cell inactivated Schizosaccharomyces pombe that produces a novel form of selenium called selenoneine was used as a prebiotic supplement in this study. Selenoneine is a novel selenium-containing molecule with an antioxidant activity, suggesting it has potential to improve the production of fish when used as a functional ingredient in aquafeeds. To investigate if this selenium-enriched S. pombe can strengthen the production metrics, modulate the surface and internal microbiome, and improve the health status of fish, an 8-week fish feeding trial was conducted. A commercial feed was supplemented with no addition (control), 5 g Kg−1 (0.5%), or 10 g Kg−1 (1.0%) of selenium-enriched S. pombe. Fish were harvested at the middle (week 4) and end of the trial (week 8). There were no significant differences (p > 0.05) in food conversion ratio, condition factor, or survival of fish during the trial. The microbiome also remained stable during the experiment. No effect (p > 0.05) was observed in the growth performance of the fish at week 4; however, at week 8 fish that were fed 0.5% yeast had a significantly higher weight gain (p < 0.05), hepatosomatic index, and viscerosomatic index than the fish fed control and 1.0% diets. At week 4, the concentration of plasma lysozyme in fish fed 0.5% yeast was significantly higher (p < 0.05) than the control fish and fish fed the 1.0% diet. No significant differences (p > 0.05) were observed in glutathione peroxidase activity in the liver, kidney, or plasma of fish fed experimental diets at the two different sampling times. However, the superoxide dismutase activity of plasma was significantly higher with the 0.5% diet than the control and 1.0% fed fish at week 4. At week 8, both the 0.5% and 1.0% diets led to significant increases (p < 0.05) in superoxide dismutase activity in the plasma of fish when compared to the control diet. This study demonstrates that supplementation of aquafeed with selenoneine-producing S. pombe can improve the growth, immune response, and oxidative status of fish. Thus, this ingredient holds a promising potential to enhance sustainability within the aquaculture industry.

Chiral Cobalt(II) Complex Catalyzed Asymmetric [2,3]-Sigmatropic Rearrangement of Allylic Selenides with α-Diazo Pyrazoleamides

Organoselenium compounds, due to their high structural diversity, special function, and biological activities, have drawn attention in synthetic chemistry. Herein, a novel example of chiral N,N′-di...

Females are more susceptible than male mice to thermal hypernociceptive behavior induced by early-life bisphenol-A exposure: Effectiveness of diphenyl diselenide

Humans are ubiquitously exposed to bisphenol A (BPA), one of the most used synthetic monomers for manufacturing polycarbonate plastics. BPA exposure leads to abnormal nociceptive perception and neuroinflammation in rodents. This study investigated whether diphenyl diselenide (PhSe)2, a pleiotropic selenium-containing molecule, would be effective against the hypernociceptive behavior induced by the early-life BPA exposure to mice. Three-week-old male and female Swiss mice received intragastrically BPA (5 mg/kg) from 21st to 60th postnatal day. After, the mice received by the intragastric route (PhSe)2 (1 mg/kg) once a day for seven days. After the last day of treatment, the mice performed the hot plate and tail immersion tests. The cerebral cortex samples were used to determine the levels of proteins related to apoptosis and inflammation. The results demonstrated that females were more susceptible than male mice to thermal hypernociception induced by early-life exposure to BPA. (PhSe)2 was effective against the reduction in the latency to paw and tail withdrawal induced by BPA exposure in female mice. Furthermore, (PhSe)2 restored the impairment in the levels of inflammatory proteins (COX-2, IL-1β, and p-JNK/JNK) but not those of apoptosis in the cerebral cortex of female mice exposed to BPA. Collectively, these data showed that females were more susceptible to thermal hypernociceptive behavior induced by early-life exposure to BPA than male mice. The administration of (PhSe)2 reduced thermal hypernociceptive behavior, a sex independent effect, in BPA-exposed mice. (PhSe)2 modulated inflammatory protein levels in the cerebral cortex of female mice exposed to BPA.

952P - Results of phase I clinical trial of high doses of seleno-l-methionine (SLM) in sequential combination with axitinib in previously treated and relapsed clear cell renal carcinoma (ccRCC) patients

BackgroundThe overexpression of hypoxia induced factor 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses and schedules of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. MethodsThis is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with standard dose axitinib to patients with metastatic ccRCC. Primary endpoint is safety; secondary endpoint is efficacy including overall response rate, progression free survival and overall survival. ResultsTwelve evaluable patients (pts) with metastatic ccRCC who progressed on one or more prior lines of treatment were enrolled. The first 3 pts were treated at 4000 µg, the second and third 3 pts were treated at 2500 and 3000 µg respectively. Additional 3 pts were added to 4000 µg. No dose limiting toxicity was seen. Most common AEs included fatigue, diarrhea, hypertension, nausea, anorexia, cough, proteinuria and weight loss. Of the 4000 µg cohort, 2 pts achieved complete response with ongoing responses at 31 and 29 months, 1pt had partial response (PR) for 24 months. Of the 2500 µg cohort, 1pt with ongoing PR for 21 months. The 3000 µg cohort, one pt has ongoing PR for 12 months. ConclusionsSLM of 4000 µg is safe and the recommended phase 2 dose in combination with standard dose axitinib. The combination has promising efficacy with phase 2 trial is ongoing. Further data to be presented at the meeting. Clinical trial identificationNCT02535533. Legal entity responsible for the studyYousef Zakharia. FundingHolden Comprehensive Cancer Centre. DisclosureY. Zakharia: Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche Diagnostics; Advisory / Consultancy: Novartis; Advisory / Consultancy: Jansen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Castle Bioscience; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Bayer; Advisory / Consultancy: Array. M. Milhem: Advisory / Consultancy: Amgen; Advisory / Consultancy: Trieza; Advisory / Consultancy: Biontech; Advisory / Consultancy: Blueprint Medicines Corporation; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Array. All other authors have declared no conflicts of interest.

Preliminary results of phase I clinical trial of high doses of seleno-L-methionine (SLM) in sequential combination with axitinib in previously treated and relapsed clear cell renal cell carcinoma (ccRCC) patients.

660 Background: The overexpression of hypoxia induced factor 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with standard dose axitinib to patients with metastatic RCC. Primary endpoint is safety. Secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 12 evaluable patients (pts) with metastatic RCC who progressed on one or more prior lines of treatment were enrolled. The first 3 pts were treated at 4000 µg, the second and third 3 pts were treated at 2500 and 3000 µg respectively. Additional 3 pts were added to 4000 µg. No dose limiting toxicity (DLT) was seen. Most common AEs included fatigue, diarrhea, hypertension, nausea, anorexia, cough, proteinuria and weight loss. Of the 4000 µg cohort, 2 pts achieved CR with ongoing responses at 31 and 29 months, 1 pt had PR for 24 months and 1 had PD at 3 months, 2 pts are not assessed yet. Of the 2500 µg cohort, 1 pt with ongoing PR for 21 months, 1 pt had stable disease for 6 months, and 1 pt had PD at 2 months. The 3000 µg cohort, one pt has ongoing PR for 12 months; another pt had PR lasting 10 months, the 3rd pt had SD for 4 months. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy. Further data including biomarkers will be presented at the meeting. Clinical trial information: NCT02535533.

Selenium-functionalized metal-organic frameworks as enzyme mimics

The development of artificial enzyme mimics has been rapidly growing in recent years, and it is attracting increasing attention owing to their remarkable advantages over natural enzymes. Herein, we developed a general and facile method to fabricate efficient glutathione peroxidase (GPx) mimics by grafting selenium-containing molecules (phenylselenylbromide, PhSeBr) to a Zr(IV)-based UiO-66-NH2 framework. In the presence of glutathione (GSH) serving as substrate, the fabricated UiO-66-Se catalysts can catalyze the reduction of hydroperoxides. The as-prepared UiO-66-Se systems show good catalytic activity over three cycles. These high-efficiency GPx mimic metal-organic frameworks (MOFs) are endowed with excellent thermal and structural stability, providing a promising avenue for the development of artificial enzyme mimics.

Phase1 clinical trial of high doses of Seleno-L-methionine (SLM), in sequential combination with axitinib in previously treated and relapsed clear cell renal cell carcinoma (ccRCC) patients.

630 Background: The overexpression of hypoxia induced factor (HIF) 1a/2a in ccRCC leads to up-regulation of vascular endothelial growth factor (VEGF) that results in increased angiogenesis, tumor metastasis, and treatment resistance. Using several preclinical xenograft models, it has been demonstrated that therapeutic doses and schedules of the selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocysteine (MSC) caused enhanced degradation of HIF1α/2α, down-regulation of oncogenic miRNA-210 and 155, up-regulation tumor suppressor miRNA-664 and LET-7b, and stabilization of tumor vasculature, yielding higher tumor drug uptake and protection from toxic side effects when combined with chemotherapeutic and VEGF-targeted agents. Methods: This is a phase I (3+3 design) dose finding trial of SLM (2500, 3000 or 4000 µg) given orally twice daily for 14 days, followed by once a day in combination with the standard dose of axitinib to patients with metastatic RCC. Primary endpoint is safety, secondary endpoint is efficacy including overall response rate (ORR), progression free survival (PFS) and overall survival (OS). Results: To date, 9 patients with metastatic RCC; who failed one or more prior lines of treatment; are enrolled. The first 3 patients were treated at 4000 µg, the second and third 3 patients were treated at 2500 and 3000 µg respectively. No dose limiting toxicity (DLT) is encountered. Six patients are evaluable to date. Of the 4000 µg cohort, 2 patients achieved complete remission (CR) at 18 and 20 months, 1 patient with partial response (PR) at 19 month. Of the 2500 µg cohort, one patient achieved PR at 9 months, 1 patient had stable disease for 9 months before progression, and 1 patient had disease progression at 4 months. The 3000 µg cohort is too early to evaluate for efficacy. Of interest the 4000μg SLM dose yielded a plasma selenium concentration of 40-50μM which is comparable with SLM dose determined synergistic with anti-cancer drugs in preclinical models. Conclusions: High dose SLM is safe in combination with axitinib, with promising efficacy, further data to be presented at the meeting. Clinical trial information: NCT02535533.

Abstract 2237: Novel selenium-containing aspirin molecule AS-10 suppresses androgen receptor signaling and induces apoptosis of LNCap prostate cancer cells

Abstract Aspirin as the best known low cost Non-Steroidal Anti-inflammatory drug (NSAID) has been associated with lowering risk of colorectal cancer, in addition to its cardiovascular health benefit at low dose (baby Aspirin) and over-the-counter pain medication. Through an innovative research program aiming at enhancing the bioactivities of NSAIDs by incorporation of selenium, we have discovered AS-10 as a novel Aspirin-selenium compound with promising anti-cancer drug-like properties in terms of potency enhancement (at least 3 orders of magnitude compared to Aspirin), selective cytotoxicity against cancer cells including majority of NCI-60 panel, while sparing normal moue embryonic fibroblasts in cell culture screening assays. Preliminary toxicology study in mice had shown a wide safety margin. Extensive structure-activity relationship investigation suggested a novel structural basis, instead of releasable selenium, that accounted for the striking potency. To investigate the potential chemopreventive attributes of AS-10 against prostate carcinogenesis, we selected LNCaP cells (wild type p53, functional androgen receptor, AR) to examine the growth suppression and apoptosis responses in cell culture. The rationale for choosing LNCaP cell line as target cells rests in the fact that precancerous prostatic lesions that are the intended targets of chemoprevention as well as early stage prostate cancer retain wild type p53 and they are critically dependent on AR signaling for survival. Our results show that cell viability (MTT) test detected a potent growth inhibition of LNCaP cells in a time and concentration dependent manner, with an EC50 in range of 1.7 to 2.5 μM range compared with Aspirin in the millimolar range. Western blot analysis of AS-10 treated LNCaP cells showed decreased protein level of AR and its best known downstream target prostate specific antigen (PSA) in a concentration-dependent manner. In addition, AS-10 treatment led to increased Annexin V staining, caspase 3/7 activity, and PARP cleavage, all indicators of caspase-mediated apoptosis. Furthermore, AS-10 treatment increased the expression of p53-DNA damage response (DDR) proteins such as p21 (canonical target of p53) and p-H2A.X (a marker for DNA strand breaks). Given that our earlier work with pancreatic cancer cells has indicated a rapid induction of reactive oxygen species (ROS) by AS-10 exposure, we hypothesize that ROS generation may be involved in LNCaP cells to trigger the DDR and apoptosis responses. In summary, our findings suggest AS-10 as a potential chemopreventive agent for prostate carcinogenesis. Citation Format: Deepkamal N. Karelia, Sangyub Kim, Srinivasa Ramisetti, Cheng Jiang, Shantu Amin, Arun K. Sharma, Junxuan Lu. Novel selenium-containing aspirin molecule AS-10 suppresses androgen receptor signaling and induces apoptosis of LNCap prostate cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2237. doi:10.1158/1538-7445.AM2017-2237

Treatment with a selenium-platinum compound induced T-cell acute lymphoblastic leukemia/lymphoma cells apoptosis through the mitochondrial signaling pathway.

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is an aggressive hematological disorder that is sensitive to chemotherapy; however, it exhibits frequent relapse rates. Platinum-containing therapeutics are the first-line salvage regimens used in the treatment of relapsed or refractory T-ALL/LBL. The selenium-platinum compound EG-Se/Pt is obtained from the combination of selenium-containing molecules (EG-Se) with cisplatin (CDDP); however, its anticancer properties have been poorly investigated. In the present study, the Cell Counting Kit-8 assay was used to evaluate the inhibitory effect of treatment with EG-Se/Pt on cell viability. Cell cycle distribution, apoptosis, reactive oxygen species (ROS) content and the mitochondrial membrane potential were analyzed using flow cytometry. Intracellular platinum content was detected using inductively coupled plasma mass spectrometry. Caspase activity was determined using a colorimetric assay. The expression of several proteins associated with apoptosis was analyzed using western blotting. The results of the present study demonstrated that treatment with EG-Se/Pt increased the inhibition of Jurkat and Molt-4 T-ALL/LBL cell viability compared with CDDP, and induced apoptosis and cell cycle arrest. The intracellular platinum content of T-ALL/LBL cells treated with EG-Se/Pt was increased compared with that of T-ALL/LBL cells treated with CDDP. EG-Se/Pt-induced apoptosis was mediated by caspase and ROS levels through the activation of the mitochondrial signaling pathway. The results of the present study suggest that EG-Se/Pt is a potential therapeutic candidate for the treatment of T-ALL/LBL.

Direct access to β-seleno sulfones at room temperature through selenosulfonylation of alkenes

A new protocol has been developed for the formation of C−Se and C−S bonds by the direct selenosulfonylation of alkenes. This protocol is operationally simplistic, has a wide substrate scope, uses readily available seleno and sulfonyl sources, and is amenable to gram-scale synthesis. This reaction represents a significant addition to the limited number of reactions available for the intermolecular selenide difunctionalization of alkenes and would be useful for the synthesis of sulfur- and selenium-containing molecules

Detection of Intracellular Selenol-Containing Molecules Using a Fluorescent Probe with Near-Zero Background Signal

Selenocysteine (Sec), encoded as the 21st amino acid, is the predominant chemical form of selenium that is closely related to various human diseases. Thus, it is of high importance to identify novel probes for sensitive and selective recognition of Sec and Sec-containing proteins. Although a few probes have been reported to detect artificially introduced selenols in cells or tissues, none of them has been shown to be sensitive enough to detect endogenous selenols. We report the characterization and application of a new fluorogenic molecular probe for the detection of intracellular selenols. This probe exhibits near-zero background fluorescence but produces remarkable fluorescence enhancement upon reacting with selenols in a fast chemical reaction. It is highly specific and sensitive for intracellular selenium-containing molecules such as Sec and selenoproteins. When combined with flow cytometry, this probe is able to detect endogenous selenols in various human cancer cells. It is also able to image endogenous selenol-containing molecules in zebrafish under a fluorescence microscope. These results demonstrate that this molecular probe can function as a useful molecular tool for intracellular selenol sensing, which is valuable in the clinical diagnosis for human diseases associated with Sec-deficiency or overdose.

On the reliability of determination of energies of HOMO and LUMO levels in organic semiconductors from electrochemical measurements. A simple picture based on the electrostatic model

Relations between energies of ionized levels (HOMO and LUMO levels) obtained from photoelectron spectroscopy (UPS and IPES) of molecular solids, and oxidation (reduction) potentials of respective molecules dissolved in non-aqueous solvents are re-examined. Several classes of molecules are taken into account: polycyclic aromatic hydrocarbons, fullerenes, aromatic amines and anhydrides, sulfur- and selenium-containing molecules, coordination complexes, etc. It is demonstrated that the equations, commonly employed to evaluate the solid state energies of ionized levels from electrochemical measurements, should be modified. Based on literature data gathered for over 100 molecules, empirical correlations are determined allowing for estimation of the solid-state ionization energies and electron affinities from electrochemical experiments. The correlation coefficients depend on the selection of molecules involved and potential range but for the most common combination of these two parameters the following correlations are proposed: Ic = (1.15 ± 0.09) × (eπox) + (4.79 ± 0.07) eV, and Ac = (1.18 ± 0.05) × (eπred) + (4.83 ± 0.10) eV. A model is put forward explaining the course of the correlations.