Accelerated remyelination and immune modulation by the EBI2 agonist 7α,25-dihydroxycholesterol analogue in the cuprizone model.

Research indicates a role for EBI2 receptor in remyelination, demonstrating that its deficiency or antagonism inhibits this process. However, activation of EBI2 with its endogenous ligand, oxysterol 7α,25-dihydroxycholesterol (7α,25OHC), does not enhance remyelination beyond the levels observed in spontaneously remyelinating tissue. We hypothesized that the short half-life of the natural ligand might explain this lack of beneficial effects and tested a synthetic analogue, CF-7α,25OHC, in the cuprizone model.

Convenient and efficient N-methylation of secondary amines under solvent-free ball milling conditions.

In the present work, we report the development of a rapid, efficient, and solvent-free procedure for the N-methylation of secondary amines under mechanochemical conditions. After optimization of the milling parameters, a vibrational ball mill was used to synthesize 26 tertiary N-methylated amine derivatives in a short time of 20 min (30 Hz frequency) and high yields ranging from 78 to 95%. An exception was compounds having a hydroxyl group in their structure, for which a decrease in reaction efficiency was observed.

Surprising Radiolytic Stability of 8-Thiomethyladenine in an Aqueous Solution.

8-Thiomethyladenine (ASCH), a potentially radiosensitizing modified nucleobase, has been synthesized in a reaction between 8-thioadenine and methyl iodide. Despite favorable dissociative electron attachment (DEA) characteristics, the radiolysis of an aqueous solution of ASCH with a dose of X-ray amounting to as much as 300 Gy leads to no effects. Nevertheless, crossed electron-molecule beam experiments in the gas phase on ASCH confirm the theoretical findings regarding the stability of its radical anion, namely, the most abundant reaction channel is related to the dissociation of the S-CH bond in the respective anion.

Development of potent and effective SARS-CoV-2 main protease inhibitors based on maleimide analogs for the potential treatment of COVID-19.

In the present work, we report a new series of potent SARS-CoV-2 Main Protease (Mpro) inhibitors based on maleimide derivatives. The inhibitory activities were tested in an enzymatic assay using recombinant Mpro (3CL Protease from coronavirus SARS-CoV-2). Within the set of new Mpro inhibitors, demonstrated the highest activity in the enzymatic assay with an IC value of 8.

Dissociative Electron Attachment to 5-Iodo-4-thio-2'-deoxyuridine: A Potential Radiosensitizer of Hypoxic Cells.

In the search for effective radiosensitizers for tumor cells, halogenated uracils have attracted more attention due to their large cross section for dissociation upon the attachment of low-energy electrons. In this study, we investigated dissociative electron attachment (DEA) to 5-iodo-4-thio-2'-deoxyuridine, a potential radiosensitizer using a crossed electron-molecule beam experiment coupled with quadrupole mass spectrometry. The experimental results were supported by calculations on the threshold energies of formed anions and transition state calculations.

Electron-Induced Decomposition of 5-Bromo-4-thiouracil and 5-Bromo-4-thio-2'-deoxyuridine: The Effect of the Deoxyribose Moiety on Dissociative Electron Attachment.

When modified uridine derivatives are incorporated into DNA, radical species may form that cause DNA damage. This category of molecules has been proposed as radiosensitizers and is currently being researched. Here, we study electron attachment to 5-bromo-4-thiouracil (BrSU), a uracil derivative, and 5-bromo-4-thio-2'-deoxyuridine (BrSdU), with an attached deoxyribose moiety via the N-glycosidic (N1-C) bond.

Intramolecular Proton Transfer in the Radical Anion of Cytidine Monophosphate Sheds Light on the Sensitivities of Dry vs Wet DNA to Electron Attachment-Induced Damage.

Single-strand breaks (SSBs) induced via electron attachment were previously observed in dry DNA under ultrahigh vacuum (UHV), while hydrated electrons were found not able to induce this DNA damage in an aqueous solution. To explain these findings, crossed electron-molecular beam (CEMB) and anion photoelectron spectroscopy (aPES) experiments coupled to density functional theory (DFT) modeling were used to demonstrate the fundamental importance of proton transfer (PT) in radical anions formed via electron attachment. Three molecular systems were investigated: 5'-monophosphate of 2'-deoxycytidine (dCMPH), where PT in the electron adduct is feasible, and two ethylated derivatives, 5'-diethylphosphate and 3',5'-tetraethyldiphosphate of 2'-deoxycytidine, where PT is blocked due to substitution of labile protons with the ethyl residues.

Design, synthesis and biological evaluation of novel -phosphorylated and -phosphorylated tacrine derivatives as potential drugs against Alzheimer's disease.

In this work, we designed, synthesised and biologically investigated a novel series of 14 - and -phosphorylated tacrine derivatives as potential anti-Alzheimer's disease agents. In the reaction of 9-chlorotacrine and corresponding diamines/aminoalkylalcohol we obtained diamino and aminoalkylhydroxy tacrine derivatives. Next, the compounds were acid to give final products - and - that were characterised by H, C, P NMR and MS.

Development of Sulfamoylated 4-(1-Phenyl-1-1,2,3-triazol-4-yl)phenol Derivatives as Potent Steroid Sulfatase Inhibitors for Efficient Treatment of Breast Cancer.

We present here the advances achieved in the development of new sulfamoylated 4-(1-phenyl-1-1,2,3-triazol-4-yl)phenol derivatives as potent steroid sulfatase (STS) inhibitors for the treatment of breast cancer. Prompted by promising biological results and in silico analysis, the initial series of similar compounds were extended, appending a variety of m-substituents at the outer phenyl ring. The inhibition profiles of the newly synthesized compounds were evaluated using a radioisotope enzymatic assay and, together with the preceding reported derivatives, using a radioisotope assay in MCF-7 cells.

Hydration of Simple Model Peptides in Aqueous Osmolyte Solutions.

The biology and chemistry of proteins and peptides are inextricably linked with water as the solvent. The reason for the high stability of some proteins or uncontrolled aggregation of others may be hidden in the properties of their hydration water. In this study, we investigated the effect of stabilizing osmolyte-TMAO (trimethylamine -oxide) and destabilizing osmolyte-urea on hydration shells of two short peptides, NAGMA (-acetyl-glycine-methylamide) and diglycine, by means of FTIR spectroscopy and molecular dynamics simulations.

Novel 1,2,3-Triazole Derivatives as Mimics of Steroidal System-Synthesis, Crystal Structures Determination, Hirshfeld Surfaces Analysis and Molecular Docking.

Herein, we present the synthesis and crystal structures determination of five 4-(1-phenyl-1-1,2,3-triazol-4-yl)phenol derivatives containing halogen atoms, -, which may be used as an excellent mimic of steroids in the drug development process. Good quality crystals obtained for all of the synthesized compounds allowed the analysis of their molecular structures. Subsequently, the determined crystal structures were used to calculate the Hirshfeld surfaces for each of the synthesized compounds.

Electron-Induced Decomposition of Uracil-5-yl (,-dimethylsulfamate): Role of Methylation in Molecular Stability.

The incorporation of modified uracil derivatives into DNA leads to the formation of radical species that induce DNA damage. Molecules of this class have been suggested as radiosensitizers and are still under investigation. In this study, we present the results of dissociative electron attachment to uracil-5-yl -(,-dimethylsulfamate) in the gas phase.

New potent steroid sulphatase inhibitors based on 6-(1-phenyl-1-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives.

In the present work, we report a new class of potent steroid sulphatase (STS) inhibitors based on 6-(1-phenyl-1-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives. Within the set of new STS inhibitors, 6-(1-(1,2,3-trifluorophenyl)-1-1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate demonstrated the highest activity in the enzymatic assay inhibiting the STS activity to 7.98% at 0.

Novel 1,2,4-Oxadiazole Derivatives in Drug Discovery.

Five-membered 1,2,4-oxadiazole heterocyclic ring has received considerable attentionbecause of its unique bioisosteric properties and an unusually wide spectrum of biological activities.Thus, it is a perfect framework for the novel drug development. After a century since the1,2,4-oxadiazole have been discovered, the uncommon potential attracted medicinal chemists'attention, leading to the discovery of a few presently accessible drugs containing 1,2,4-oxadiazoleunit.

Recent progress in the development of steroid sulphatase inhibitors - examples of the novel and most promising compounds from the last decade.

The purpose of this review article is to provide an overview of recent achievements in the synthesis of novel steroid sulphatase (STS) inhibitors. STS is a crucial enzyme in the biosynthesis of active hormones (including oestrogens and androgens) and, therefore, represents an extremely attractive molecular target for the development of hormone-dependent cancer therapies. The inhibition of STS may effectively reduce the availability of active hormones for cancer cells, causing a positive therapeutic effect.

New potent STS inhibitors based on fluorinated 4-(1-phenyl-1-[1,2,3]triazol-4-yl)-phenyl sulfamates.

A series of fluorinated analogs based on the frameworks of 4-(1-phenyl-1-[1,2,3]triazol-4-yl)-phenyl sulfamates have been synthesized as steroid sulfatase (STS) inhibitors. The design of chemical structures of new potential STS inhibitors was supported by molecular docking techniques to identify potential interactions between inhibitors and amino acid residues located in the STS active site. The STS inhibitory potency was evaluated on STS isolated from human placenta.

Synthesis and Cholinesterase Inhibitory Activity of N-Phosphorylated/ N-Tiophosphorylated Tacrine.

Background: Alzheimer's disease (AD) is progressive and irreversible neurodegenerative disorder. Current pharmacotherapy is not able to stop progression of the disease and can only improve cognitive functions. Therefore, new drugs are being sought that will slow down the development of the disease.

Novel steroid sulfatase inhibitors based on N-thiophosphorylated 3-(4-aminophenyl)-coumarin-7-O-sulfamates.

In the present work, we described convenient methods for the synthesis of N-thiophosphorylated 3-(4-aminophenyl)-coumarin-7-O-sulfamates as steroid sulfatase (STS) inhibitors. To design the structures of the potential STS inhibitors, molecular modeling techniques were used. A computational docking method was used to determine the binding modes of the synthesized inhibitors as well as to identify potential interactions between specified functional groups on the inhibitors and the amino acid residues present in the active site of the enzyme.

Synthesis and biological evaluation of fluorinated N-benzoyl and N-phenylacetoyl derivatives of 3-(4-aminophenyl)-coumarin-7-O-sulfamate as steroid sulfatase inhibitors.

In the present work, we report convenient methods for the synthesis of 3-(4-aminophenyl)-coumarin-7-O-sulfamate derivatives N-acylated with fluorinated analogues of benzoic or phenylacetic acid as steroid sulfatase (STS) inhibitors. The design of these potential STS inhibitors was supported by molecular modeling techniques. Additionally, computational docking methods were used to determine the binding modes of the synthesized inhibitors and to identify potential interactions between inhibitors and amino acid residues located in the active site of STS.

Synthesis and biological evaluation of N-acylated tyramine sulfamates containing C-F bonds as steroid sulfatase inhibitors.

Steroid sulfatase (STS) is responsible for the hydrolysis of biologically inactive sulfated steroids into their active un-sulfated forms and promotes the growth of various hormone-dependent cancers (e.g., breast cancer).

Phosphoroorganic Metal Complexes in Therapeutics.

The present mini-review highlights recent developments on antitumor activity of metal-based therapeutics which have been a subject of researches for the last few decades. In 1965, Rosenberg found that during an electrolysis on platinum electrodes a complex of Pt is generated which inhibited to a great extent a binary fission in Escherichia coli bacteria. This discovery started a new chapter in medicinal chemistry and the interesting properties of cisplatin were soon applied in cancer therapy especially in curing genitourinary tumors.

Steroid Sulfatase Inhibitors Based on Phosphate and Thiophosphate Flavone Analogs.

A series of phosphate and thiophosphate flavone derivatives were synthesized and biologically evaluated in vitro for inhibition of steroid sulfatase (STS) activity. The described synthesis includes the straightforward preparation of 7-hydroxy-2-phenyl-4H-chromen-4-one 3a, 2-(4-fluorophenyl)-7-hydroxy-4H-chromen-4-one 3b, 7-hydroxy-2-(4-(trifluoromethyl)phenyl)-4H-chromen-4-one 3c, 7-hydroxy-2-(p-tolyl)-4H-chromen-4-one 3d modified with different phosphate or thiophosphate moieties. The inhibitory properties of the synthesized compounds were tested against human placenta STS.

Synthesis and Biological Evaluation of Fluorinated 3-Phenylcoumarin-7-O-Sulfamate Derivatives as Steroid Sulfatase Inhibitors.

In the present work, we report the initial results of our study on a series of 3-phenylcoumarin sulfamate-based compounds containing C-F bonds as novel inhibitors of steroid sulfatase. The new compounds are potent steroid sulfatase inhibitors, possessing more than 10 times higher inhibitory potency than coumarin-7-O-sulfamate. In the course of our investigation, compounds 2b and 2c demonstrated the highest inhibitory effect on the enzymatic steroid sulfatase assay; both had IC50 values of 0.

Synthesis and biological evaluation of thiophosphate tricyclic coumarin derivatives as steroid sulfatase inhibitors.

Steroid sulfatase (STS) enzyme inhibition is an important approach to the management of hormone-dependent breast cancer. In this paper, we report convenient methods for the synthesis and biological evaluation of thiophosphate tricyclic coumarin analogs exhibiting STS activity. The described methods are based on the straightforward preparation of 7-hydroxy-2,3-dihydro-1H-cyclopenta[c]chromen-2-one, 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one, and 3-hydroxy-8,9,10,11-tetrahydro-7H-cyclohepta[c]chromen-6-one and their further modification by the introduction of various thiophosphate moieties.

Synthesis of bicoumarin thiophosphate derivatives as steroid sulfatase inhibitors.

Based on the frameworks of 7-hydroxy-2,3-dihydro-1H-cyclopenta[c]chromen-4-one, 3-hydroxy-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one and 3-hydroxy-8,9,10,11-tetrahydro-7H-cyclohepta[c]chromen-6-one, a series of bicoumarin thiophosphate analogs have been synthesized and biologically evaluated. Additionally, their binding modes have been modeled using docking techniques. The inhibitory properties of the synthesized compounds were tested against the STS isolated from human placenta.