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.

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.

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.

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.

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.

Anticancer Properties of Amino Acid and Peptide Derivatives of Mycophenolic Acid.

Background: Although Mycophenolic Acid (MPA) is applied as prodrugs in clinic as an immunosuppressant, it also possesses anticancer activity. MPA acts as Inosine-5'-Monophosphate Dehydrogenase (IMPDH) inhibitor, where the carboxylic group at the end of the side chain interacts with Ser 276 of the enzyme via hydrogen bonds. Therefore, MPA derivatives with other polar groups indicated high inhibition too.

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.

Immunosuppressive properties of amino acid and peptide derivatives of mycophenolic acid.

Mycophenolic acid (MPA) was coupled with amino acids and biologically active peptides including derivatives of tuftsin to modify its immunosuppressive properties. Both amino acid unit in the case of simple MPA amides and modifications within peptide moiety of MPA - tuftsin conjugates influenced the observed activity. Antiproliferative potential of the obtained conjugates was investigated in vitro and MPA amides with threonine methyl ester and conjugate of MPA with retro-tuftisin occurred to be more selective against PBMC in comparison to parent MPA.

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.

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 antimicrobial activity of amino acid and peptide derivatives of mycophenolic acid.

The series of 16 novel amino acid and peptide mycophenolic acid (MPA) derivatives was obtained as potential antibacterial agents. Coupling of MPA with respective amines was optimized with condensing reagents such as EDCI/DMAP and T3P/TEA. Amino acid analogs were received both as methyl esters and also with the free carboxylic group.

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.

Phosphate and thiophosphate biphenyl analogs as steroid sulfatase inhibitors.

In the present work, we report convenient methods for the synthesis and biological evaluation of phosphate and thiophosphate biphenyl derivatives exhibiting steroid sulfatase (STS) activity. The described synthesis is based on straightforward preparation of biphenyl-4-ol and 4'-hydroxy-biphenyl-4-carboxylic acid ethyl ester modified with various phosphate or thiophosphate moieties. The inhibitory effects of these compounds were tested on STS isolated from human placenta and led to two compounds of interest, 5a and 5d with IC50 values of 28.

5,5-Dimethyl-2-methyl-seleno-1,3,2-dioxaphospho-rinan-2-one.

The title compound, C(6)H(13)O(3)PSe, was obtained in the reaction of 5,5-dimethyl-2-oxo-2-seleno-1,3,2-dioxaphospho-r-inane potassium salt with methyl iodide. The seleno-methyl group is in the axial position in relation to the six-membered dioxaphospho-rinane ring.

Synthesis and structural investigation of N-acyl selenophosphoramides.

2-Amino-2-seleno-5,5-dimethyl-1,3,2-dioxaphosphorinane reacts with acyl chlorides (4-chlorobenzoyl chloride or pivaloyl chloride) yielding the respective N-acyl selenophosphoramides. These derivatives do not isomerise to the related selenocarbonyl imides. X-ray study of N-(4-chlorobenzoyl)-2-amino-2-seleno-5,5-dimethyl-1,3,2-dioxaphosphorinane indicates that the selenium atom is placed in the equatorial position.

O-4-Chloro-benzoyl diphenyl-seleno-phosphinate.

The title compound, C(19)H(14)ClO(2)PSe, was obtained in the reaction of the diphenyl-monoseleno-phosphinic acid ammonium salt with 4-chloro-benzoyl chloride. The dihedral angle between the P-bonded aromatic rings is 72.64 (14)°.

O-Pivaloyl diphenyl-seleno-phosphinate.

The title compound, C(17)H(19)O(2)PSe, was obtained in the reaction of the diphenyl-monoseleno-phosphinic acid ammonium salt with pivaloyl chloride. The P-Se bond length of 2.0769 (11) Å is normal, while the P-O bond length of 1.

1,3-Alternate 25,27-dibenzoiloxy-26,28-bis-[3-propyloxy]-calix[4]arene-bonded silica gel as a new type of HPLC stationary phase.

A new 1,3-alternate 25,27-dibenzoiloxy-26,28-bis-[3-propyloxy]-calix[4]arene-bonded silica gel stationary phase (1,3-Alt CalixBn) has been prepared and used for the separation of aromatic positional isomers by high-performance liquid chromatography (HPLC). The effect of organic modifier content and pH of the mobile phase on retention and selectivity of these compounds were studied. Application examples were provided for separation of purine and pyrimidine bases and non-steroidal anti-inflammatory drugs.