Diselenonicotinamide (DSNA), a synthetic organoselenium compound, was evaluated for its radioprotective effect in cellular models. A clonogenic assay in Chinese Hamster Ovary (CHO) cells and an apoptosis assay in murine splenic lymphocytes indicated that pre-treatment with DSNA at a concentration of 25 μM significantly protected them from radiation-induced cell death. Upon irradiation (1-12 Gy), dose-response studies were carried out under similar treatment conditions, and its dose modification factor (DMF) was estimated to be 1.26. Furthermore, DSNA showed its radioprotective effect, even when administered after exposure to radiation. Mechanistic investigation revealed that DSNA increased the intracellular levels of GPx and GSH in irradiated cells. In line with this observation, the addition of a pharmacological inhibitor of GPx cycle, abrogated the activity of DSNA. The radioprotective effect of DSNA was also complemented by its ability to prevent radiation-induced DNA damage as monitored by micronucleus and γ-H2AX assays. Furthermore, treatment with DSNA did not show much change in the expressions of Nrf2 dependent genes (γ-GCL and HO-1), but the presence of a pharmacological inhibitor of Nrf2 abrogated the radioprotective activity of DSNA against cell death and DNA damage. Additionally, ATRA treatment also inhibited the DSNA-mediated up-regulation of a repair gene RAD51, suggesting possible involvement of basal Nrf2 in the anti-genotoxic effect of DSNA. In conclusion, the present study demonstrates radioprotection by a synthetic organoselenium compound containing nutritionally important moieties like selenium and nicotinamide.
Functionalized tetrahydropyran (THP) rings are important building blocks and ubiquitous scaffolds in many natural products and active pharmaceutical ingredients (API). Among various established methods, the Prins reaction has emerged as a powerful technique in the stereoselective synthesis of the tetrahydropyran skeleton with various substituents, and the strategy has further been successfully applied in the total synthesis of bioactive macrocycles and related natural products. In this context, hundreds of valuable contributions have already been made in this area, and the present review is intended to provide the systematic assortment of diverse Prins cyclization strategies, covering the literature reports of the last twenty years (from 2000 to 2019), with an aim to give an overview on exciting advancements in this area and designing new strategies for the total synthesis of related natural products.
The asymmetric total synthesis of optically pure (–)‐gracilamine (1) was achieved by employing a bioinspired approach. The strategy involved elaboration of 3a‐arylhexahydroindole 7, a designed precursor, to 3a‐formylarylhexahydroindole 5, which upon heating with l‐leucine ethyl ester gave (–)‐1 efficiently.
A series of amphiphilic conjugates of dihydroxy selenolane (DHS) and monoamine selenolane (MAS), which we had previously reported to inhibit lipid peroxidation and assist the oxidative protein folding reaction respectively in cell free systems, were evaluated for cytotoxicity, associated mechanisms and antioxidant effects in cells. Our results indicated that a fatty acid/alkyl group of variable chain lengths (C) as a lipophilic moiety of the DHS/MAS conjugates not only improved their ability to incorporate within the plasma membrane of cells but also modulated their cytotoxicity. In the concentration range of 1-50 μM, C conjugates were non-toxic whereas the long chain (≥C) conjugates showed significant cytotoxicity. The induction of toxicity investigated by the changes in membrane leakage, fluidity, mitochondrial membrane potential and annexin-V-propidium iodide (PI) staining by using flow cytometry revealed plasma membrane disintegration and subsequent induction of necrosis as the major mechanism. Further, the conjugates of DHS and MAS also showed differential as well as nonlinear tendency in cytotoxicity with respect to chain lengths and this effect was attributed to their self-aggregation properties. Compared with the parent compounds, C conjugates not only exhibited better antioxidant activity in terms of the induction of selenoproteins such as glutathione peroxidase 1 (GPx1), GPx4 and thioredoxin reductase 1 (TrxR1) but also protected cells from the AAPH induced oxidative stress. In conclusion, the present study suggests the importance of hydrophilic-lipophilic balance (HLB) in fine tuning the toxicity and activity of bioinspired amphiphilic antioxidants.
Functionalized hydroindole (1), a common chiral synthon, for versatile transformations to synthesize a broad range of Amaryllidaceae alkaloids (AAs) including (-)-crinine, (-)-crinane, (-)-amabiline, (+)-mesembrine, (-)-maritidine, (-)-oxomaritidine, and (+)-mesembrane is reported. Scaffold 1 is found as a prime structural motif in a wide variety of the AAs and is a novel synthon toward designing a divergent route for the synthesis of these natural products. This is established in a few steps, starting from a chiral aza-bicyclo-heptene sulfone scaffold (2) via conjugate addition and concomitant stereoselective ring opening with allylmagnesium bromide, a key step that generates a crucial quaternary stereocenter, fixing the stereochemistry of the rest of the molecule at an early stage. One carbon truncation followed by intramolecular reductive amination led to the desired core 1 in a multigram scale.
Objectives To examine the antiproliferative effect of a rationally designed, novel noscapine analogue, 9-((perfluorophenyl)methylene) aminonoscapine, '9-PAN') on MDA-MB-231 breast cancer cell line, and to elucidate the underlying mechanism of action. Methods The rationally designed Schiff base-containing compound, 9-PAN, was characterized using IR, NMR and mass spectra analysis. The effect of the compound on cell viability was studied using an MTT assay. Cell cycle and cell death analyses were performed using flow cytometry. Binding interactions of 9-PAN with tubulin were studied using spectrofluorometry. Reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) were investigated using the probes, DCFDA and rhodamine-123, respectively. Immunofluorescence imaging was used to visualize cellular microtubules. Key findings 9-PAN inhibited cell proliferation (IC 50 of 20 AE 0.3 µM) and colony formation (IC 50 , 6.2 AE 0.3 µM) by arresting the cells at G 2 /M phase of the cell cycle. It bound to tubulin in a concentration-dependent manner without considerably altering the tertiary conformation of the protein or the polymer mass of the microtubules in vitro. The noscapinoid substantially damaged cellular microtubule network and induced cell death, facilitated by elevated levels of ROS. Conclusions 9-PAN exerts its antiproliferative effect by targeting tubulin and elevating ROS level in the cells.
The aim of the present study is to evaluate the radioprotective effect of low-dose selenium supplementation (multiple administrations) on radiation toxicities and mortality induced by lethal dose of whole-body irradiation (WBI). For this, BALB/c mice received sodium selenite (4 μg/kg body wt) intraperitoneally for five consecutive days and subjected to WBI at an absorbed dose of 8 Gy (Co, 1 Gy/min). Administration of sodium selenite was continued even during the post irradiation days three times a week till the end of the experiment. The radioprotective effect was evaluated in terms of the improvement in 30 days post irradiation survival, protection from DNA damage, and biochemical and histological changes in radiosensitive organs. The results indicated that low-dose sodium selenite administration did not protect the mice from radiation-induced hematopoietic and gastrointestinal injuries and subsequent mortality. However, it significantly prevented the radiation-induced genotoxicity or DNA damage in peripheral leukocytes. Further sodium selenite administration modulated the messenger RNA (mRNA) expression of GPx1, GPx2, and GPx4 in the spleen and intestine differentially and led to a significant increase in GPx activity (∼1.5 to 2-folds) in these organs. In line with this observation, sodium selenite administration reduced the level of lipid peroxidation in the intestine. In conclusion, our study shows that low-dose sodium selenite supplementation can be an effective strategy to prevent WBI-induced genotoxicity but may not have an advantage against mortality sustained during nuclear emergencies.
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