Stanisław Boryczka

Synthesis, structure and cytotoxic activity of new acetylenic derivatives of betulin.

A new series of betulin derivatives containing one or two pharmacophores bearing an acetylenic and carbonyl function at the C-3 and/or C-28 positions has been synthesized and characterized by 1H- and 13C-NMR, IR, MS and elemental analyses. The crystal structure of 28-O-propynoylbetulin was determined by X-ray structural analysis. All new compounds, as well as betulin, were tested in vitro for their antiproliferative activity against human SW707 colorectal, CCRF/CEM leukemia, T47D breast cancer, and against murine P388 leukemia and Balb3T3 normal fibroblasts cell lines. Most of the compounds showed better cytotoxicity than betulin and cisplatin used as reference agent. 28-O-Propynoylbetulin was the most potent derivative, being over 500 times more potent than betulin and about 100 times more cytotoxic than cisplatin against the human leukemia (CCRF/CEM) cell line, with an ID50 value of 0.02 μg/mL.

A new preparation of alpha-oxo-thioesters by electro-oxidation of diaryl disulfides in the presence of alkynes

A mechanism for the electrochemical oxidation of diaryl disulfides in organic solvents is proposed. A difference is observed according to the nature of the solvent. In dichloromethane and in neutral conditions it is a two-electron process leading to the postulated cation Ar-S + . By reactions in situ with terminal alkynes in the presence of nucleophiles, α-oxothioesters of the type R-CO-CO-S-Ar were obtained.

Synthesis and antiproliferative activity in vitro of novel (2-butynyl)thioquinolines

The series of new acetylenic thioquinolines containing propargyl, 2-butynyl, 4-bromo-2-butynyl, and 4-hydroxy-2-butynyl groups has been prepared and tested for antiproliferative activity in vitro against human [SW707 (colorectal adenocarcinoma), CCRF/CEM (leukemia)] and murine [P388 (leukemia), B16 (melanoma)] cancer lines. All the compounds obtained exhibited antiproliferative activity. The most active compounds 7, 16, 17, and 19 have the ID(50) values ranging from 0.2 to 4.6 microg/ml comparable to that of cisplatin used as reference compounds.

RP TLC determination of the lipophilicity of anticancer-active propargyl thioquinolines

The lipophilicity of fifteen anticancer-active propargyl thioquinolines has been determined by reversed-phase thin-layer chromatography with mixtures of acetone and Tris buffer, pH 7.4, as mobile phases. The RM values of the compounds decreased linearly with increasing concentration of acetone in the mobile phases. The partition coefficients (log P) of the propargyl thioquinolines were calculated by use of the ScilogP program. Comparison of RM0 and log PScilogP values enabled calculation of clog P values. It was found that the clog P values of the compounds correlated with their in vitro anticancer activity, expressed as ID50 [μg mL−1], against a breast cancer cell line (T47D).

Influence of betulin and 28-O-propynoylbetulin on proliferation and apoptosis of human melanoma cells (G-361).

INTRODUCTION Pentacyclic triterpenes are a group of compounds known to have anticancer activity. One of the best characterized triterpenes is betulin, which can be isolated from bark of birch trees and modified into new compounds with various interesting medical properties. Betulin is involved in activation of the caspase cascade and promotes cell death. The aim of the study was to investigate the effect of betulin and its acetylenic derivative, 28-O-propynoylbetulin, on proliferation and apoptosis in a human melanoma cell line. MATERIALS AND METHODS The G-361 melanoma cell line was used. To evaluate growth arrest and caspase-3 activity, cells were treated with betulin and its derivative at a wide range of concentrations from 0.1 to 10 μg/mL. RESULTS Betulin and 28-O-propynoylbetulin inhibited cell proliferation in a concentration-dependent manner. The cell cycle analysis revealed an increase of the sub-G1 cell fraction (representing dead cells) after incubation of cells with betulin and 28-O-propynoylbetulin. The observed cytotoxic effects were more pronounced for 28-O-propynoylbetulin. Activity of caspase-3 in 28-O-propynoylbetulin treated cells was nearly 2-fold greater compared to cells incubated with betulin. DISCUSSION Our results show that betulin and 28-O-propynoylbetulin were effective in inhibition of cell growth and induction of apoptosis in a human melanoma cell line. The addition of the propynoyl group at the C-28 hydroxyl group of betulin led to a greater proapoptotic and antiproliferative effect in comparison to unmodified betulin. These observations suggest that the obtained derivative is a potent anti-melanoma agent.

X-ray structure of 3′,4-dimethylthio-3,4′-diquinolinyl sulfide

The title compound (C20H16N2S3) is monoclinic, witha=31.550(9),b=8.504(3),c=14.745(3) Å,β=114.14(3)°,Z=8 and space groupC2/c. The structure was solved by direct methods and refined toR=0.038 for 3012 reflections. The molecule exists in an uncommon conformation. Two quinoline moieties are nearly perpendicular to each other (80.9(3)°). Both methylthio groups have different orientation (the 4-SCH3 group is nearly perpendicular and the 3′-SCH3 is nearly coplanar to the quinoline moieties). Two pairs of sulfur atoms in ortho-positions remain in very close contact. The conformation of the molecule explains an unusual1H NMR spectrum.

Crystal structure of betulinic acid-DMSO solvate

Abstract The crystal structure of betulinic acid-DMSO (1:1) solvate has been determined. The betulinic acid, [3β-hydroxy-lup-20(29)-en-28-oic acid, C30H48O3] is considered as a promising natural agent for the clinical treatment for various types of cancer. Crystals of betulinic acid for X-ray structural analysis were grown from a DMSO-water (9:1, v/v) solution. Betulinic acid-DMSO (1:1) solvate crystallizes in the orthorhombic symmetry the P212121 space group, Z = 4. The unit cell parameters are as follows: cell lengths a = 6.9417(2) Å, b = 13.8559(5) Å, c = 31.6232(10) Å, V = 3041.63(17) Å3. Betulinic acid molecules are hydrogen bonded to DMSO molecules. The weak intermolecular hydrogen bonds and van der Waals interactions are present in the crystal structure. The crystal and molecular structures of betulinic acid-DMSO solvates are discussed with reference to betulin and betulinic acid derivatives.

X-Ray Diffraction and Infrared Spectroscopy of N,N- Dimethylformamide and Dimethyl Sulfoxide Solvatomorphs of Betulonic Acid

X-ray diffraction and infrared spectroscopy measurements for the N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) solvatomorphs of betulonic acid (BA) were investigated. BA [3-oxolup-20(29)-en-28-oic acid, C(30)H(46)O(3)] exhibits a wide spectrum of biological activities and is considered to be a promising natural agent for the treatment of various cancer diseases. BA as a noncrystalline substance was obtained by oxidation of betulin. Crystal structures and the spectral data allowed analysis of hydrogen bonding (H-bonding), molecular conformation, and crystal packing differences in the solvatomorphs. Crystals of BA solvates were grown from the DMF-acetone (1:10, v/v) and DMSO-water (9:1, v/v) solutions. BA-DMF (1:1) solvate crystallizes in the monoclinic P2(1) space group, Z = 2. The unit cell parameters are as follows: cell lengths a = 13.2458(5) Å, b = 6.6501(2) Å, c = 17.9766(7) Å, and β = 110.513(4)°. BA-DMSO (1:1) solvate crystallizes in the orthorhombic P2(1)2(1)2(1) (Z = 4) space group with the following unit cell parameters: a = 6.6484(4) Å, b = 13.3279(8) Å, and c = 32.6821(19) Å. Conformational analysis of the six-membered rings, cyclopentane ring, and isopropenyl group showed differences in comparison with other betulin derivatives examined earlier. For both solvates, the intermolecular packing arrangement was governed mainly by H-bonds. The shortest H-bonds with D···A distances of 2.604 and 2.657 Å, and almost linear DH···A connection occurred between OH of carboxylic group of BA and oxygen atoms from O=C and O=S groups of DMF and DMSO, respectively.

Synthesis, molecular docking study, and evaluation of the antiproliferative action of a new group of propargylthio- and propargylselenoquinolines

This study describes the synthesis of a new group of halogenopropargylthio-, dipropargylthio-, and halogenopropargylseleno-quinoline derivatives. The ability of all of the synthesized compounds to inhibit the proliferation of the T-47D, MCF-7, MDA-MB-231, and SNB-19 cell lines was determined with the WST-1 assay. The normal fibroblast cell line (HFF-1) was used as a control. The cytotoxic properties of these new, modified propargylquinoline derivatives were comparable to those of cisplatin. The most active compounds, 4,7-dipropargylthiquinoline (8b) and 7-chloro-4-propargylselenoquinoline (5b), were docked into the binding site of human CYP1A1 and CYP1B1. Our data indicate that these derivatives may present promising chemotherapeutic agents, possibly targeting CYP1s pathway.

C≡C—H⋯N hydrogen bonding in 3-methylthio-4-propargylthioquinoline

The title compound, C13H11NS2, contains a C≡C—H⋯N hydrogen bond to a pyridine-type N atom, with a C⋯N distance of 3.305 (4) A and an H⋯N distance of 2.28 A. This is one of the shortest C—H⋯N hydrogen bonds known.