Studies on preparation of 64Cu using (n,γ) route of reactor production using medium flux research reactor in India

⁶⁴Cu (t_1/2 12.7 h) is a versatile radionuclide owing to its unique decay scheme and exhibits three types of decay electron capture (41%), β⁻ (40%), β⁺ (19%) that is useful in nuclear medicine applications. Different batches of natural copper oxide (CuO) and 99.9% enriched ⁶³CuO targets were irradiated in research reactors at a neutron flux of 6.6 × 10¹² n cm⁻² s⁻¹ for duration of 3 days. Irradiated samples dissolved in hydrochloric acid solution were measured in HPGe-MCA system, the activity of ⁶⁴Cu, co-produced radionuclide impurities and radionuclide purity was determined. Average specific activity of 254 GBq ⁶⁴Cu per g Cu and ~348 GBq ⁶⁴Cu per g Cu was recorded at the end of irradiation from natural and enriched CuO targets, respectively.     

Dielectric characterisation of a ferroelectric liquid crystalline material having SmA*–SmC*–SmBh* phase sequence

Thermodynamical, optical and dielectric characterisation of a material possessing ferroelectric SmC* and hexatic SmB* phases has been carried out. Phase identification has been done by miscibility studies. From the dielectric studies, a relaxation mechanism is observed in the low MHz region of the SmA* phase, which is related to the tilt fluctuation (soft mode) of the directors. In the SmC* phase, another collective relaxation mechanism has been observed in the kHz region, which is related to the phase fluctuation (Goldstone mode) of the directors. In the SmB_h* phase, 2-weak relaxation modes are observed in the kHz and MHz frequency range, respectively, due to individual molecular rotations.     

On the practical aspects of large-scale production of 177Lu for peptide receptor radionuclide therapy using direct neutron activation of 176Lu in a medium flux research reactor: the Indian experience

This paper accentuates on the practical aspects and intricate technicalities involved in the large-scale production of ¹⁷⁷Lu with specific activity >740 GBq mg^?1 following (n,γ)¹⁷⁷Lu route in a medium flux (~1.2 × 10¹⁴ n cm^?2 s^?1 thermal neutron) research reactor. The implication of target burn-up on the specific activity of ¹⁷⁷Lu during irradiation was discussed in detail. ¹⁷⁷Lu obtained from this route has been extensively utilized for targeted therapy in patients with neuroendocrine tumor in India. The important details available from our experience, as well as technical know-how, would be of considerable value for institutions planning to pursue ¹⁷⁷Lu production through (n,γ)¹⁷⁷Lu route.     

Rapid analysis of titer,aggregate, and intact mass of antibody therapeutics using automated multi-dimensional liquid chromatography coupled with native mass spectroscopy

Monoclonal antibodies are tetrameric complex proteins, primarily produced using mammalian cell culture. Attributes such as titer, aggregates, and intact mass analysis are monitored during process development/optimization. In the present study, a novel workflow such that the Protein-A affinity chromatography is performed in the first dimension for purification and titer estimation, whereas size exclusion chromatography is employed in the second dimension to characterize size variants using native mass spectrometry. The present workflow offers a significant advantage over the traditionally used standalone Protein-A affinity chromatography followed by size exclusion chromatography analysis in that it can monitor these four attributes in 8 min while requiring a minimal sample size (10–15 μg) and not requiring any manual peak collection. In contrast, the traditional standalone approach requires manual collection of eluted peaks in Protein-A affinity chromatography followed by buffer exchange to a mass-compatible buffer, which can take up to 2–3 h with considerable risk of sample loss, degradation, and induced modifications. As the biopharma industry moves to make analytical testing efficient, we believe that the approach proposed here would be of significant interest due to its ability to monitor multiple process and product quality attributes in a single workflow and via rapid analysis.     

The determination of glutathione-4-hydroxynonenal (GSHNE), E-4-hydroxynonenal (HNE), and E-1-hydroxynon-2-en-4-one (HNO) in mouse liver tissue by LC-ESI-MS

Glutathione (GSH) conjugation of 4-hydroxy-2(E)-nonenal (HNE) is an efficient means of cellular detoxification. HNE is a byproduct of lipid peroxidation which has shown toxicity but also signaling roles. E-1-hydroxynon-2-en-4-one (HNO) is another byproduct of lipid peroxidation which has the same molecular weight as HNE. This study presents the LC-MS detection of GS-HNE, HNE, and HNO in tissue samples without derivatization and with minimal sample preparation. Tissue samples were taken from wild-type mice and knock-out mice, which have been bred without the RLIP76 transfer protein. Extraction procedures were developed to determine GS-HNE and HNE levels in the mouse liver tissue. A gradient elution LC-MS method was developed for GS-HNE analysis using electrospray ionization and selected ion monitoring (SIM). The HNE/HNO method involves isocratic elution due to instability issues. Higher levels of GSHNE, HNE, and HNO were found in the knock-out animals, due to the absence of the RLIP76 transport mechanism.     

Organocatalytic enantioselective synthesis of β-blockers: (S)-propranolol and (S)-naftopidil

An efficient enantioselective synthesis of β-adrenergic blockers (S)-propranolol and (S)-naftopidil with >98% ee using an l-proline-catalyzed α-aminoxylation of an aldehyde as a key step is described.     

Scaffold hopping for identification of novel D2 antagonist based on 3D pharmacophore modelling of illoperidone analogs

The dopamine D(2) receptor is involved in the etiology of a number of disorders, such as Parkinson's disease, Huntington's Chorea, tardive dyskinesia and schizophrenia. Antagonism of D(2) receptors is implicated in the treatment of various psychiatric disorders. In order to understand essential structural features required for D(2) antagonism, this research article elaborates on the generation of a four-point 3D pharmacophore model which was extracted from a series of 45 novel 3-[[(aryloxy)alkyl]piperidinyl]-1,2-benzisoxazole derivatives. The best pharmacophore model generated consisted of four PRRR features: a positively charged group (P), and three aromatic rings (R). Based on the model generated, a statistically valid 3D-QSAR with good predictability (Q(2) = 0.756) was derived. For the validation of the pharmacophore hypothesis, active compounds were docked against the 3D structure of the D(2) receptor which was constructed through homology modeling. Further, the derived pharmacophore was used as a query to search the Zinc 'clean drug-like' database. Hits retrieved were passed progressively through filters, such as fitness score, predicted activity and docking scores. The resulting hits present new scaffolds with a strong potential for D(2) antagonist.     

Targeting Akt/NF-κB/p53 Pathway and Apoptosis Inducing Potential of 1,2-Benzenedicarboxylic Acid,Bis (2-Methyl Propyl) Ester Isolated from Onosma bracteata Wall. against Human Osteosarcoma (MG-63) Cells

Onosma bracteata Wall. is an important medicinal and immunity-enhancing herbs. This plant is commonly used in the preparation of traditional Ayurvedic drugs to treat numerous diseases. Inspired by the medicinal properties of this plant, the present study aimed to investigate the antiproliferative potential and the primary molecular mechanisms of the apoptotic induction against human osteosarcoma (MG-63) cells. Among all the fractions isolated from O. bracteata, ethyl acetate fraction (Obea) showed good antioxidant activity in superoxide radical scavenging assay and lipid peroxidation assay with an EC₅₀ value of 95.12 and 80.67 µg/mL, respectively. Silica gel column chromatography of ethyl acetate (Obea) fraction of O. bracteata yielded a pure compound, which was characterized by NMR, FTIR, and HR-MS analysis and was identified as 1,2-benzene dicarboxylic acid, bis (2-methyl propyl) ester (BDCe fraction). BDCe fraction was evaluated for the antiproliferative potential against human osteosarcoma MG-63, human neuroblastoma IMR-32, and human lung carcinoma A549 cell lines by MTT assay and exhibited GI₅₀ values of 37.53 μM, 56.05 μM, and 47.12 μM, respectively. In MG-63 cells, the BDCe fraction increased the level of ROS and simultaneously decreased the mitochondria membrane potential (MMP) potential by arresting cells at the G₀/G₁ phase, suggesting the initiation of apoptosis. Western blotting analysis revealed the upregulation of p53, caspase3, and caspase9 while the expressions of p-NF-κB, p-Akt and Bcl-xl were decreased. RT-qPCR studies also showed upregulation in the expression of p53 and caspase3 and downregulation in the expression of CDK2, Bcl-2 and Cyclin E genes. Molecular docking analysis displayed the interaction between BDCe fraction with p53 (−151.13 kcal/mol) and CDK1 (−133.96 kcal/mol). The results of the present work suggest that the BDCe fraction has chemopreventive properties against osteosarcoma (MG-63) cells through the induction of cell cycle arrest and apoptosis via Akt/NF-κB/p53 pathways. This study contributes to the understanding of the utilization of BDCe fraction in osteosarcoma treatment.