Comparing the DNA-damage RBE of intraoperative and conventional electron beams using a hybrid simulation approach.

PURPOSE: Employing electron beam for radiotherapy purposes now has been established as one of the standard cancer treatment modalities. Both dedicated intraoperative and conventional electron beams can be employed in patient irradiation. Due to the differences between accelerating structure and electron beam delivery of dedicated intraoperative radiotherapy (IORT) machines and conventional ones, the initial energy spectra of the produced electron beam by these machines may be different. Accordingly, this study aims to evaluate whether these spectral differences can affect the relevant relative biological effectiveness (RBE) values of intraoperative and conventional electron beams. MATERIALS AND METHODS: A hybrid Monte Carlo simulation approach was considered. At first, the head LIAC12 machine (as an IORT accelerator) and Varian 2100C/D (as a conventional accelerator) were simulated by MCNPX code and electron energy spectra at different depths and off-axis distances were scored for two nominal electron energies of 6 and 12 MeV at the field sizes of 6 and 10 cm. Then, the calculated spectra were imported to MCDS code to estimate the induced DNA-damage RBE values. Finally, the obtained RBE values for intraoperative and conventional electron beams were compared together. RESULTS: The results showed that the RBE values of the intraoperative electron beam are superior to those obtained for conventional electron beam at the same energy/field size combination. Variations of the depth can regularly affect the RBE value for both conventional and intraoperative electron beams, while no ordered variation trend was observed for RBE with changing the off-axis distance. Variations of electron energy and field size can also influence the RBE value for both types of studied electron beams. CONCLUSIONS: From the results, it can be concluded the structural differences between the dedicated IORT and conventional Linacs can lead to distinct initial electron energy spectra for intraoperative and conventional electron beams. These physical differences can finally lead to different RBE values for intraoperative and conventional electron beams at the same energy and field size.

Domino protocol for the synthesis of diversely functionalized derivatives of a novel fused pentacyclic antioxidant/anticancer fluorescent scaffold: Pyrazolo[5'',1'':2',3']pyrimido[4',5':5,6][1,4]thiazino[2,3-b]quinoxaline.

Rising to the challenge of formidable multi-step reaction needed for the synthesis of polycyclic compounds, an efficient one-pot two-step procedure for the synthesis of densely functionalized novel pyrazolo[5″,1'':2',3']pyrimido[4',5':5,6] [1,4]thiazino[2,3-b]quinoxalines from synthetically accessible starting materials 6-bromo-7-chloro-3-cyano-2-(ethylthio)-5-methylpyrazolo[1,5-a]pyrimidine, 3-aminoquinoxaline-2-thiol and some readily accessible alkyl halides was established. The domino reaction pathway involves cyclocondensation/N-alkylation sequence in K2CO3/N,N-dimethyl formamide under heating condition. DPPH free radical scavenging activity of all synthesized pyrazolo[5″,1'':2',3']pyrimido[4',5':5,6][1,4]thiazino[2,3-b]quinoxalines was evaluated to determine their antioxidant potentials. IC50 values were recorded in the range of 29-71 µM. N-benzyl substituted derivative represented the most effective antioxidant activity as well as antiproliferative activity against MCF-7 cells. Moreover, fluorescence in solution for these compounds exhibited strong red emission in the visible region (λflu. = 536-558 nm) with good to excellent quantum yields (61-95%). Due to their interesting fluorescence properties, these novel pentacyclic fluorophores can be used as fluorescent markers and probes for studies in biochemistry and pharmacology.

Synthesis, molecular docking and dynamics studies of pyridazino[4,5-b]quinoxalin-1(2H)-ones as targeting main protease of COVID-19.

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created a crisis in public health. Because, the 3CLpro, the main protease of SARS-CoV-2, possesses a critical role in coronavirus replication, many efforts have been devoted to developing various inhibitors to prevent the fast spread of COVID-19. In the current work, a number of various pyridazino[4,5-b]quinoxalin-1(2H)-one derivatives bearing thiadiazine and thiadiazole fragments has been prepared via a straightforward and practical strategy involving the reaction of 2-(ethoxycarbonyl)-3-formylquinoxaline 1,4-dioxide with thiocarbohydrazide under reflux conditions. To determine the bioavailability of pyridazino[4,5-b]quinoxalin-1(2H)-one derivatives, Lipinski's rule of five has been carried out. Regarding this rule, none of the synthesized compounds exhibit any deviation from Lipinski's rule of five. Furthermore, molecular docking and molecular dynamics approaches have been implemented to figure out the potential interactions of products with SARS-CoV-2 main protease. The outcomes of molecular docking studies demonstrate that the phenyl and nitrophenyl substituted pyridazino[4,5-b]quinoxalin-1(2H)-one show the lowest binding affinity among the other compounds, indicating a favorable orientation in the active site of the chymotrypsin-like cysteine protease. In addition, the MD simulation performed to evaluate the stability of the protein-ligand complex represents that the average binding energy of the nitrophenyl complex is less than that of the phenyl complex. Therefore, according to the in silico results, the inhibitory effect of the nitrophenyl complex is more significant than the phenyl complex.Communicated by Ramaswamy H. Sarma.

A Dimroth rearrangement approach for the synthesis of selenopheno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidines with cytotoxic activity on breast cancer cells.

New selenopheno[2,3-e][1,2,4]triazolo[1,5-c]pyrimidine derivatives have been synthesized via Dimroth rearrangement by cyclocondensation of 7-cyano-4-hydrazinyl-6-(pyrrolidin-1-yl)selenopheno[3,2-d]pyrimidine with electrophilic carbons of either orthoesters in acetic acid or carbon disulfide in pyridine followed by S-alkylation. All the newly synthesized products have been structurally elucidated. The in vitro anticancer screening of the tricyclic Se-containing heterocycles was accomplished against human breast carcinoma MCF-7 cancerous cell line and L929 cells. Anticancer results revealed that the S-hexyl-substituted compound with an IC50 value of 158.9 µM in 72 h was foremost among others in cytotoxic potency. In the following order, S-pentyl and S-ethyl-substituted derivatives with IC50 values of 216.1 and 396.5 µM were second and third efficient compounds as in anticancer activity, respectively. The inhibitory effects of the mentioned compounds were less on the growth of L929 cells.

Synthesis, characterization and in vitro anticancer evaluations of two novel derivatives of deferasirox iron chelator.

Iron (Fe) chelation therapy was initially designed to alleviate the toxic effects of excess Fe evident in Fe-overload diseases. However, the novel toxicological properties of some Fe chelator-metal complexes have shifted significant attention to their application in cancer chemotherapy. The present study investigates the new role of deferasirox as an anticancer agent due to its ability to chelate with iron. Because of aminoacids antioxidant effect, deferasirox and its two novel amino acid derivatives have been synthesized through the treatment of deferasirox with DCC as well as glycine or phenylalanine methyl ester. All new compounds have been characterized by elemental analysis, FT-IR NMR and mass spectrometry. Therefore, the cytotoxicity of these compounds was screened for antitumor activity against some cell lines using cisplatin as a comparative standard by MTT assay and Flow cytometry. The impact of iron in the intracellular generation of reactive oxygen species was assessed on HT29 and MDA-MB-231 cells. The potential of the synthesized iron chelators for their efficacy to protect cells against model oxidative injury induced was compared. The reactive oxygen species intracellular fluorescence intensity were measured and the result showed that the reactive oxygen species intensity after iron incubation increased while after chelators incubation the reactive oxygen species intensity were decreased significantly. Besides, the effect of the synthesized compounds on mouse fibroblast cell line (L929) was simultaneously evaluated as control. The pharmacological results showed that deferasirox and its two novel aminoacid derivatives were potent anticancer agents.

PYRIMIDOOXADIAZINE AND TRIAZOLOPYRIMIDOOXADIAZINE DERIVATIVES: SYNTHESIS AND CYTOTOXIC EVALUATION IN HUMAN CANCER CELL LINES.

In vitro antiproliferative activities of some pyrimido[4,5-e][1,3,4]oxadiazine and [1,2,4]triazolo[4',3':1,2]pyrimido[4,5-e][1,3,4]oxadiazine derivatives were examined in human malignant cancer cell lines. All synthesized compounds inhibited the growth of malignant cells in a dose dependent manner, but among them 1,5,7-trimethyl-3-phenyl-1H-[1,2,4]triazolo[4',3':1,2]pyrimido[4,5-e][1,3,4]oxadiazine and [(1,5-dimethyl-3-phenyl-1H-[1,2,4]triazolo[4',3':1,2]pyrimido[4,5-e][1,3,4]oxadiazin-7-yl)sulfanyl]acetonitrile, both with triazole moiety, were found to be more effective than other compounds; they also induced a sub-G1 peak in the flow cytometry histogram of treated cells compared to controls, indicating that apoptotic cell death is involved in toxicity they induce. The results showed that compounds with triazole moiety fused to pyrimido[4,5-e] [1,3,4]oxadiazine derivatives are more active than those bearing chlorine or pyrrolidine groups at C-7 position.