Current Chemical Biology - Volume 16, Issue 1, 2022

Compounds based on two different elements, selenium and platinum, have been attracting researchers to deploy them in chemotherapy of human cancers. Selenium, as a micronutrient, plays many important roles in human biology. Different research groups have been developing both inorganic and organoselenium compounds for potential use in the treatment of diseases, including cancer. New synthetic designs are emerging to develop selenium compounds either as chemopreventive or chemotherapeutic agents. Platinum is another important element in cancer therapy. Platinum-based drugs are the first line of treatment for many cancers. Attracted by the fact that chalcogens are excellent ligands for platinum, new ideas are emerging to develop selenium-bound platinum compounds as cancer therapeutics. In this direction, our group has made an effort to develop stable seleno-platinum compounds to explore their anti-cancer potential.

Low-molecular-mass selenium (LMM-Se) molecules, such as ebselen and diphenyldiselenide, have many biological and potential therapeutic activities; however, little is known about their mechanism of action. It has been stipulated that LMM-Se can modify the physiological chemistry of endogenous thiol (–SH) and selenol (–SeH) groups by different mechanisms. Generically, LMM-Se compounds are poor mimetics of glutathione peroxidase (GPx) enzyme, suggesting that their thiol-modifier effect is more reasonable to justify their biological action. Unfortunately, the LMM-Se interactions with their targets are relatively non-specific. Here, the action of LMM-Se as potential therapeutic agents will be discussed, as well as the bottleneck and myths about their potential use as therapeutic agents.

Background: Many organoselenium compounds are well known for their applications in various fields. However, some of the organoselenium compounds, like selenosemicarbazones, due to difficulties in their synthesis are not much explored. Herein, we present the synthesis and characterization of five different new selenosemicarbazones. Objective: The study aimed to carry out the synthesis and characterization of novel selenosemicarbazones, a type of Schiff bases. Methods: Selenosemicarbazones are synthesized in a single step, i.e., acid-catalyzed condensation reaction between ketones and hydrazine hydrate in the presence of potassium selenocyanate (KSeCN). Results: Butyrophenone, 4-phenyl 2-butanone, 2-acetonaphthone, 4-nitroacetophenone and menthone were reacted with in-situ generated selenosemicarbazide, which led to the formation of respective selenosemicarbazones. These organoselenium derivatives of Schiff bases have been characterized by mass spectrometry, proton, carbon and selenium NMR. Conclusion: The yields of synthesized butyrophenone, 4-phenyl 2-butanone, 2-acetonaphthone, 4- nitroacetophenone, and menthone selenosemicarbazones varied in between 44 to 65%. The synthesis strategy involved one-pot synthesis of selenosemicarbazone without isolation of toxic selenosemicarbazide.

Introduction: An efficient synthesis of hexakis(alkylthio/selenomethyl)benzenes [(RSCH2)6C6 and (RSeCH2)6C6] (1-14) (where, R= ⁿPr, ⁱPr, ⁿBu, ⁱBu, ^sBu, ^tBu, ⁿPent, ⁱPent, and 2- Methyl-1-butyl) by the reaction of hexakis(bromomethyl)benzene with alkylthio or alkylseleno (RS- /RSe-) anions is demonstrated. Methods: They have been characterized by physicochemical and spectroscopic methods, including single-crystal X-ray crystallography. The balances between multiple [C(sp³)-H…S] or [C(sp³)-H…Se] intramolecular interactions in these species appear to decide their stability. Preliminary spectroscopic (UV-vis. and fluorescence) data on the behavior of alkylchalcogeno substituted hexa-benzenes in solution revealed their potential as ion-sensing species and function as highly selective ionophores for Ag⁺ and Hg2⁺ ions recognition. Results: In situ, (Hg-S) and (Hg-Se) bond formation on interaction with the chosen hexa-species (2 and 10) and Hg2⁺ cation revealed a unique ‘turn-off’ or ‘turn-on’ emissive behavior, and these functions act as reporting fluorescent tools for Hg2⁺ quantification without use of any external fluorophore. Conclusion: The present study describes an efficient and simple route for the synthesis of sterically encumbered poly-alkylthio/seleno benzenes in high purity and good yields.

Background: Thioredoxin reductase (TrxR), one of the representative selenoenzymes, is an important antioxidant enzyme suppressing oxidative stress in living organisms. At the active site of human TrxR, the presence of a Sec···His···Glu catalytic triad was previously suggested. Methods: In this study, a short selenopeptide mimicking this plausible triad, i.e., H-CUGHGE-OH (1), was designed, synthesized, and evaluated for the TrxR-like catalytic activity. Results: The molecular simulation in advance by REMC/SAAP3D predicted the preferential formation of Sec···His···Glu hydrogen bonding networks in the aqueous solution. Indeed, significant antioxidant activity was observed for 1 in the activity assay using NADPH as a reductant and H2O2 as a substrate. Tracking the reaction between 1 and GSH by ⁷⁷Se NMR revealed a reductive cleavage of the selenosulfide (Se-S) bond to generate the diselenide species. The observation suggested that in the transiently formed mixed Se-S intermediate, the NH···Se hydrogen bond between the Sec and His residues leads a nucleophilic attack of the second thiol molecule not to the intrinsically more electrophilic Se atom but to the less electrophilic S atom of the Se-S bond. Ab initio calculations for the complex between MeSeSMe and an imidazolium ion at the MP2/6-31++G(d,p) level demonstrated that NH···Se and NH···S hydrogen bonds are equally favorable as the interaction modes. Thus, the importance of the relative spatial arrangement of the Se-S bond with respect to the imidazole ring was suggested for the exertion of the TrxR-like catalytic activity. Conclusion: The proposed umpolung effect of NH···Se hydrogen bond on the reactivity of a Se-S bond will be a useful tool for developing efficient TrxR models with high redox catalytic activity.

Background: Proteins are the critical bio-molecules for cellular function and are also considered to be highly susceptible to reactive oxygen species (ROS)-induced oxidative damages. Methods: The present study aimed to evaluate some simple water-soluble aliphatic organoselenium compounds bearing different functional groups but of similar carbon chain (propyl) length for a protective effect against 2,2’-azobis-(2-amidinopropane) dihydrochloride (AAPH)-induced oxidative damage using mitochondria as an in vitro model. Results: The results indicated that APPH (20 mM) treatment of mitochondrial fraction induced protein carbonylation, leading to inactivation of redox enzymes and electron transport chain (ETC) and, ultimately the mitochondrial dysfunction. On the other hand, treatment with 0.5 mM of monoselenobutyric acid (SeBA) and monoselenopropyl alcohol (SePOH) significantly prevented APPH-induced protein carbonylation in mitochondrial fraction and restored activities of mitochondrial proteins. On the contrary, monoselenopropyl amine (SePAm) treatment at identical concentrations did not show significant protection to mitochondrial activity from AAPH-induced oxidative damages. The above results concur with the reported peroxyl radical scavenging activities of the above molecules. Conclusion: In conclusion, SeBA and SePOH are potential candidate molecules to protect proteins from oxidative damage and, therefore, can be useful for managing oxidative stress in cellular models.

Background: Antibiotic resistance of various bacterial communities remains a global burden in the healthcare industry. Biofilm formation is one of the resistance mechanisms acquired by bacterial communities in order to reverse the action of antibiotics. There is an urgent need for the discovery of novel antimicrobials and novel approaches to tackle this problem. However, it is very expensive and challenging to develop new antibiotics. Drug repurposing is an efficient strategy which reduces time and cost associated with drug discovery. Objective: In the current study, anti-microbial and antibiofilm potential of an organoselenium clinical molecule Ebselen against Neisseria mucosa has been elucidated. Methods: Ebselen Antibacterial studies include Minimum Inhibitory Concentration (MIC), growthkill, Colony Forming Unit (CFU) assays and intracellular Reactive Oxygen Species (ROS) accumulation studies. Antibiofilm studies included inhibition, eradication and cell surface hydrophobicity assays, quantification of Extracellular Polymeric Substance (EPS) and eDNA and for anti-quorum sensing activity, protease and urease enzyme activities were elucidated. Results: Ebselen showed efficient bactericidal activity as indicated by its low MIC values, bacterial growth inhibition over time and its ability to prevent clonal propagation in this bacterium. Increased accumulation of ROS in Ebselen treated cells indicates radical mediated induction of bacterial death. Interestingly, Ebselen inhibited and distorted matured biofilms by degrading the eDNA component of the EPS layer. Ebselen also attenuated quorum-sensing pathway as indicated by decreased urease and protease enzyme activities. Conclusion: Taken together, these results paved the way to repurpose Ebselen as a potential drug target to curb Neisseria mucosa infections.

Background: 2-phenyl hydrazine-1-hydroxy, 1-[2-chlorophenyl] -2-4’-methoxyphenyl] ethane and 2-oxime-1-hydroxy, 1-[2-chlorophenyl] -2-4’-methoxyphenyl] ethane derivatives of benzoin have been synthesized from 2’chloro-4-methoxy benzoin by addition reaction. Structural elucidation of the synthesized compounds was carried out through FT-IR, FT-NMR studies. The presence of electron-withdrawing and electron-donating groups enhanced the antioxidant activity, which was analyzed by 2,2-diphenyl-1-picrylhydrazyl assay, 2,2'-azino-bis (3-ethylbenzothiazoline-6- sulfonic acid) scavenging assay, hydrogen peroxide radical scavenging assay, and Ferric reducing antioxidant power assay methods. The effect of functional groups and substituents in the core structure was studied and compared with its parent compound. Aim and Objective: In this manuscript, two derivatives of benzoin viz. 2-phenyl hydrazine-1-hydroxy, 1-[2-chlorophenyl] -2-[4’-methoxyphenyl] ethane and 2-oxime-1-hydroxy, 1-[2-chlorophenyl]-2-[4’- methoxyphenyl] ethane (HA) derivatives were synthesized by benzoin condensation and followed by addition reaction to find a potential anti-oxidant agent. Materials and Methods: Qualitative analyses were determined by FT-IR and FT-NMR studies. Antioxidant activities were tested by DPPH assay, ABTS assay, and FRAP assay H2O2 methods. Results: From the obtained results, it is confirmed that the effect of withdrawing and electron releasing groups as a substituent in the core structure of parent compounds enhances the activity of antioxidant. The role of substituents is discussed in detail. Conclusion: The results of the biochemical assay reveal that the synthesized compounds serve as good free radical inhibitors and scavengers, which inhibit the oxidative reactions, and are responsible for cell damage, food spoilage, etc. The promising anti-oxidant activities are because of the effective substituents which play a prominent role in the drug industries.