With the current outbreak caused by SARS-CoV-2, vaccination is acclaimed as a public health care priority. Rapid genetic sequencing of SARS-CoV-2 has triggered the scientific community to search for effective vaccines. Collaborative approaches from research institutes and biotech companies have acknowledged the use of viral proteins as potential vaccine candidates against COVID-19. Nucleic acid (DNA or RNA) vaccines are considered the next generation vaccines as they can be rapidly designed to encode any desirable viral sequence including the highly conserved antigen sequences. RNA vaccines being less prone to host genome integration (cons of DNA vaccines) and anti-vector immunity (a compromising factor of viral vectors) offer great potential as front-runners for universal COVID-19 vaccine. The proof of concept for RNA-based vaccines has already been proven in humans, and the prospects for commercialization are very encouraging as well. With the emergence of COVID-19, mRNA-1273, an mRNA vaccine developed by Moderna, Inc. was the first to enter human trials, with the first volunteer receiving the dose within 10 weeks after SARS-CoV-2 genetic sequencing. The recent interest in mRNA vaccines has been fueled by the state of the art technologies that enhance mRNA stability and improve vaccine delivery. Interestingly, as per the “Draft landscape of COVID-19 candidate vaccines” published by the World Health Organization (WHO) on December 29, 2020, seven potential RNA based COVID-19 vaccines are in different stages of clinical trials; of them, two candidates already received emergency use authorization, and another 22 potential candidates are undergoing pre-clinical investigations. This review will shed light on the rationality of RNA as a platform for vaccine development against COVID-19, highlighting the possible pros and cons, lessons learned from the past, and the future prospects.
Abstract Die Naphthylsulfochloride (I) reagieren mit N‐Methylanilin (II) zu den Sulfonamiden 64 (III), die sich mit konz. Schwefelsäure zu den Sulfonen (IV) umlagern lassen.
Aims: The aim of this study is the evaluation of an Azomethine derivative, BCS2, for its antioxidant and anti-tumor activities against mammary carcinoma through the Nrf2- Keap1-HO-1 pathway. Background: The global prevalence of breast cancer is rising at an alarming rate. The facilitation of abnormal cell proliferation in mammary carcinoma occurs due to the disruption of signaling pathways that balance pro- and antioxidant status, thereby producing oxidative stress that disrupts genomic stability. Therefore, introducing a potent antioxidant molecule with antitumor activity is of paramount importance for treating breast cancer. Objective: Synthesis, characterization, and in-vitro, in-vivo, and in-silico evaluation of an Azomethine derivative, BCS2, for its antioxidant and anti-tumor activities against chemical carcinogen- induced mammary carcinogenesis in Sprague-Dawley rats. Methods: An azomethine derivative, 1-(4-nitrophenyl)-N-phenylmethanimine (BCS2), was synthesized and characterized based on its spectral data. The cytotoxic potential was observed on breast cancer cells, MCF-7, MDA-MB-231, and MDA-MB-468. The in vivo chemotherapeutic potential of BCS2 was established on 7,12-dimethylbenz(a)anthracene (DMBA) induced breast cancer in Sprague-Dawley (SD) rats. The effect of BCS2 on kelch-like ECH-associated protein- 1 (Keap1), Nrf2, heme oxygenase-1 (HO-1), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated-B (NF-κB) was evaluated through ELISA and qPCR techniques. Furthermore, the binding potential and stability of BCS2 with Keap-1, HO-1, and MAPK were predicted using in silico molecular docking and dynamics studies. Additionally, drug-likeness properties of BCS2 were evaluated using in silico ADMET tools. Results: BCS2 showed remarkable cytotoxic activity on MCF-7 cells followed by MDA-MB- 231 and MDA-MB-468 cells having an IC50 of 2.368μM, 4.843μM and 6.472μM respectively, without affecting normal breast cells, MCF-10A. In the DMBA-induced animal model, BCS2 showed potent antitumor potential and showed protective action on endogenous-enzymatic and non-enzymatic antioxidants in cancer-bearing animals. Marked improvement in cellular architecture and ultrastructure of breast/tumor tissues excised from experimental animals was noted through histopathological and field emission scanning electron microscopy (FESEM) analyses. Significant upregulation of antioxidant proteins, Keap1 and HO-1, and downregulation of inflammatory proteins, MAPK, and NF-κB was observed after BCS2 treatment. The in silico computational studies predicted the potent binding of BCS2 with the active pockets of Keap1, HO-1, and MAPK proteins that validated the biological findings. Conclusion: The study revealed BCS2's potent antioxidant and antitumor potential against mammary carcinoma through the Nrf2-Keap1-HO-1 signaling pathway.
A series of new molecules containing a thieno[2,3-d]pyrimidine scaffold was synthesized and characterized by adopting an efficient synthetic scheme. The effect of a free or substituted amino group at 2-position as well as an oxo-group, imidazole or 1,2,4-triazole ring at 4-position of the scaffold on the affinity and selectivity towards adenosine receptors (ARs) was evaluated. Compounds 17-19 with a free amino group at 2-position along with the presence of an imidazole/1,2,4-triazole ring at 4-position of the scaffold showed selective binding affinities for hA2A AR, whereas carbamoylation of the amino group at 2-position (in the presence of an oxo-group at 4-position of the scaffold) increased the affinity and selectivity of certain compounds (7-10) for hA3 AR. Molecular dynamic simulation study of one of the most active compound 8 (Ki hA1 > 30 μm, hA2A = 0.65 μm, and hA3 = 0.124 μm) revealed the role of important amino acid residues for imparting good affinity towards hA3 and hA2A ARs. Molecular docking studies were carried out for other compounds using the crystal structure of hA2A AR and a homology model of hA3 AR to rationalize their structure-activity relationships. The molecular docking results were in agreement with the experimental binding affinity data of ARs.
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