Betulin Phosphonates; Synthesis, Structure, and Cytotoxic Activity

International audienceBetulin derivatives are a widely studied group of compounds of natural origin due to their wide spectrum of biological activities. This paper describes new betulin derivatives, containing a phosphonate group. The allyl-vinyl isomerization and synthesis of acetylenic derivatives have been reported. Structural identification of products as E and Z isomers has been carried out using 1 H-, 13 C-, 31 P-NMR, and crystallographic analysis. The crystal structure in the orthorhombic space group and analysis of crystal packing contacts for 29-diethoxyphosphoryl-28-cyclopropylpropynoyloxy-lup-20E(29)-en-3β-ol 8a are reported. All new compounds were tested in vitro for their antiproliferative activity against human T47D (breast cancer), SNB-19 (glioblastoma), and C32 (melanoma) cell lines

Synthesis, structure and cytotoxic activity of mono- and dialkoxy derivatives of 5,8-quinolinedione

A series of 5,8-quinolinedione derivatives containing one or two alkoxy groups was synthesized and characterized by 1H- and 13C-NMR, IR and MS spectra. X-ray diffraction was used to investigate the crystal structures of 6-chloro-7-(2-cyjanoethoxy)-5,8-quinolinedione and 6,7-di(2,2,2-trifloroethoxy)-5,8-quinolinedione. All studied compounds were tested in vitro for their antiproliferative activity against three human cancer cell lines and human normal fibroblasts. Most of the compounds showed higher cytotoxicity than the starting compound, 6,7-dichloro-5,8-quinolinedione, and cisplatin, which was used as a reference agent

New acetylenic amine derivatives of 5,8-quinolinediones : synthesis, crystal structure and antiproliferative activity

Acetylenic amine derivatives of the 5,8-quinolinedione were synthesized and characterized by the1H and13C NMR, IR spectroscopy and MS spectra. Additionally, the 6- and 7-substituted allylamine-5,8-quinolinediones were synthesized for comparison purposes. The crystal structure was determined for the 6-chloro-7-propargylamine-5,8-quinolinedione and 7-chloro-6-propargylamine-5,8-quinolinedione. Additionally, the IR spectral analysis supplemented by the density functional theory (DFT) calculations were carried out. It was found that different positions of the propargylamine side chain had a distinct influence on crystal structure, formation of H-bonds and the carbonyl stretching IR bands. Correlation between the frequency separation Δv of the carbonyl IR bands and the position of the 6- and 7-substituents was found. The 7-substituted derivatives exhibited a higher frequency separation Δv. The observed correlation could provide an opportunity to use the IR spectroscopy to study substitution reactions. Cytotoxic activities against three human cancer cell lines for the 5,8-quinolinedione derivatives with different amine substituents, i.e., propargylamine, N-methylpropargylamine, 1,1-dimethylpropargylamine, allylamine and propylamine were also analysed with respect to their molecular structure

Synthesis and Structural Characterization of a New 1,2,3-Triazole Derivative of Pentacyclic Triterpene

The new 30-substituted triazole derivative of 3,28-O,O0-diacetylbetulin was obtained in the copper(I) catalyzed azide-alkyne cycloaddition (CuAAC). The title compound was characterized by NMR, IR, HR-MS, and X-ray diffraction techniques. The X-ray diffraction study showed that the 1,2,3-triazole derivative crystallizes in the orthorhombic space group P212121, Z = 4, and unit cell parameters are as follows a = 9.4860(10) Å, b = 13.9440(2) Å, and c = 30.2347(4) Å. The molecular packing is stabilized by intermolecular hydrogen interactions C-H . . . O. The Hirshfeld surface analysis showed the presence of the O . . . H interactions with a percentage of the 16.5% in the total Hirshfeld area. The MEP analysis showed that the nucleophilic regions are located near the oxygen atoms of the acyl and carbonyl groups of betulin moiety and the sulfur atom in the triazole linker. The HOMO and LUMO orbitals are located near the triazole moiety. The obtained results indicated that this new betulin derivative is more reactive with electrophilic than nucleophilic molecules

Chromatographic and computational screening of lipophilicity and pharmacokinetics of newly synthesized betulin-1,4-quinone hybrids

Lipophilicity is one of the most important parameters determining the pharmacodynamic and pharmacokinetic properties, as well as the toxicity of many compounds. The subject of the research was to determine the lipophilicity of betulin-1,4-quinone hybrids using thin layer chro-matography in reverse phase system and computer programs to calculate its theoretical models. The correlation between the experimental and theoretical values of lipophilicity was analyzed. Lipinski’s and Veber’s rules, as well as penetration through the blood–brain barrier were also determined using computer programs. For all of the analyzed values, a similarity analysis was performed. The dendrograms for the experimental and theoretical lipophilicity show that there is a correlation between them. However, the dendrograms for the experimental lipophilicity and pharmacokinetic parameters indicate that there is no correlation between the structure and the pharmacological properties. Hybrids exhibit a high biological activity against cancer cell lines, with a high level of NAD[P]H-quinone oxidoreductase (NQO1) protein. The enzymatic assay used has shown that these compounds are good NQO1 substrates, as evidenced by the increasing metabolic rates relative to that of streptonigrin. The similarity analysis has also shown that there is no correlation between lipophilicity and biological activity for the tested compounds

New phosphorus analogs of bevirimat: synthesis, evaluation of anti-HIV-1 activity and molecular docking study

Since the beginning of the human immunodeficiency virus (HIV) epidemic, many groups of drugs characterized by diverse mechanisms of action have been developed, which can suppress HIV viremia. 3-O-(3′,3′-Dimethylsuccinyl) betulinic acid, known as bevirimat (BVM), was the first compound in the class of HIV maturation inhibitors. In the present work, phosphate and phosphonate derivatives of 3-carboxyacylbetulinic acid were synthesized and evaluated for anti-HIV-1 activity. In vitro studies showed that 30-diethylphosphonate analog of BVM (compound 14a) has comparable effects to BVM (half maximal inhibitory concentrations (IC50) equal to 0.02 μM and 0.03 μM, respectively) and is also more selective (selectivity indices: 3450 and 967, respectively). To investigate the possible mechanism of antiviral effect of 14a, molecular docking was carried out on the C-terminal domain (CTD) of HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1, which was described as a molecular target for maturation inhibitors. Compared with interactions between BVM and the protein, an increased number of strong interactions between ligand 14a and protein, generated by the phosphonate group, was observed

Structural determinants influencing halogen bonding : a case study on azinesulfonamide analogs of aripiprazole as 5-HT1A, 5-HT7, and D2 receptor ligands

This work was supported by Grant KNW-1-015/K/7/O from Medical University of Silesia, Katowice, Poland. Calculations have been carried out using resources provided by Wroclaw Centre for Networking and Supercomputing (http://wcss.pl), Grant No. 382.A series of azinesulfonamide derivatives of long-chain arylpiperazines with variable-length alkylene spacers between sulfonamide and 4-arylpiperazine moiety is designed, synthesized, and biologically evaluated. In vitro methods are used to determine their affinity for serotonin 5-HT1A, 5-HT6, 5-HT7, and dopamine D2 receptors. X-ray analysis, two-dimensional NMR conformational studies, and docking into the 5-HT1A and 5-HT7 receptor models are then conducted to investigate the conformational preferences of selected serotonin receptor ligands in different environments. The bent conformation of tetramethylene derivatives is found in a solid state, in dimethyl sulfoxide, and as a global energy minimum during conformational analysis in a simulated water environment. Furthermore, ligand geometry in top-scored complexes is also bent, with one torsion angle in the spacer (τ2) in synclinal conformation. Molecular docking studies indicate the role of halogen bonding in complexes of the most potent ligands and target receptors.[SU

Lipophilicity, pharmacokinetic properties, and molecular docking study on SARS-CoV-2 target for betulin triazole derivatives with attached 1,4- quinone

A key parameter in the design of new active compounds is lipophilicity, which influences the solubility and permeability through membranes. Lipophilicity affects the pharmacodynamic and toxicological profiles of compounds. These parameters can be determined experimentally or by using different calculation methods. The aim of the research was to determine the lipophilicity of betulin triazole derivatives with attached 1,4-quinone using thin layer chromatography in a reverse phase system and a computer program to calculate its theoretical model. The physiochemical and pharmacokinetic properties were also determined by computer programs. For all obtained parameters, the similarity analysis and multilinear regression were determined. The analyses showed that there is a relationship between structure and properties under study. The molecular docking study showed that betulin triazole derivatives with attached 1,4-quinone could inhibit selected SARS-CoV-2 proteins. The MLR regression showed that there is a correlation between affinity scoring values (DG) and the physicochemical properties of the tested compounds

Spectroscopic investigations, computational analysis and molecular docking to SAR-Cov-2 targets studies of 5,8-quinolinedione attached to betulin derivatives

The 5,8-quinolinedione-betulin hybrids were investigated using spectroscopic methods as well as a variety of quantum chemical calculations in order to characterize their molecular structure. We used FT-IR and NMR spectroscopy supplemented by the density functional theory (DFT) calculations, molecular electrostatic potential (MEP) and molecular orbital (HOMO, LUMO) analyses. The experimental and calculated FT-IR spectra showed a good correlation for all compounds. Analysis of carbonyl band showed that the compounds are the 7-mono substituted. The calculated 1H NMR and 13C NMR spectra of hybrids reproduced well the experimental ones. Identification of C-6 and C-7 carbon atoms of 5,8-quinolinedione revealed the position of betulin moiety at the C-7 of 5,8-quinolinedione. Molecular electrostatic potential maps of hybrids allowed to recognize the electrophilic and nucleophilic regions within the molecules. The molecular docking study was used to examine the interaction between the 5,8-quinolinedione-betulin hybrids and the SARS-CoV-2 protein, like: Mpro and PLpro. The obtained results showed that compounds with the highest Dock Score are good anti-SARS-CoV-2 potential drug candidates

Molecular structure, in vitro anticancer study and molecular docking of new phosphate derivatives of betulin

A series of 30-diethylphosphate derivatives of betulin were synthesized and evaluated for their in vitro cytotoxic activity against human cancer cell lines, such as amelanotic melanoma (C-32), glioblastoma (SNB-19), and two lines of breast cancer (T47D, MDA-MB-231). The molecular structure and activities of the new compounds were also compared with their 29-phosphonate analogs. Compounds 7a and 7b showed the highest activity against C-32 and SNB-19 cell lines. The IC50 values for 7a were 2.15 and 0.91 M, and, for 7b, they were 0.76 and 0.8 M for the C-32 and SNB-19 lines, respectively. The most potent compounds, 7a and 7b, were tested for their effects on markers of apoptosis, such as H3, TP53, BAX, and BCL-2. For the whole series of phosphate derivatives, a lipophilicity study was performed, and the ADME parameters were calculated. The most active products were docked to the active site of the EGFR protein. The relative binding affinity of selected phosphate betulin derivatives toward EGFR was compared with standard erlotinib on the basis of ChemScore and KDEEP score. Positively, all derivatives docked inside the cavity and showed significant interactions. Moreover, a molecular dynamics study also reveals that ligands 7a,b form stable complexes and the plateau phase started after 7 ns