The Effects of the Steroids 5-Androstenediol and Dehydroepiandrosterone and Their Synthetic Derivatives on the Viability of K562, HeLa, and Wi-38 Cells and the Luminol-Stimulated Chemiluminescence of Peripheral Blood Mononuclear Cells from Healthy Volunteers.

In order to evaluate the role of substituents at 3-C and 17-C in the cytotoxic and cytoprotective actions of DHEA and 5-AED molecules, their derivatives were synthesized by esterification using the corresponding acid anhydrides or acid chlorides. As a result, seven compounds were obtained: four DHEA derivatives (DHEA 3-propionate, DHEA 3-butanoate, DHEA 3-acetate, DHEA 3-methylsulfonate) and three 5-AED derivatives (5-AED 3-butanoate, 5-AED 3,17-dipropionate, 5-AED 3,17-dibutanoate). All of these compounds showed micromolar cytotoxic activity toward HeLa and K562 human cancer cells. The maximum cytostatic effect during long-term incubation for five days with HeLa and K562 cells was demonstrated by the propionic esters of the steroids: DHEA 3-propionate and 5-AED 3,17-dipropionate. These compounds stimulated the growth of normal Wi-38 cells by 30-50%, which indicates their cytoprotective properties toward noncancerous cells. The synthesized steroid derivatives exhibited antioxidant activity by reducing the production of reactive oxygen species (ROS) by peripheral blood mononuclear cells from healthy volunteers, as demonstrated in a luminol-stimulated chemiluminescence assay. The highest antioxidant effects were shown for the propionate ester of the steroid DHEA. DHEA 3-propionate inhibited luminol-stimulated chemiluminescence by 73% compared to the control, DHEA, which inhibited it only by 15%. These data show the promise of propionic substituents at 3-C and 17-C in steroid molecules for the creation of immunostimulatory and cytoprotective substances with antioxidant properties.

Interplay of Pyrrolidine Units with Homo/Hetero Chirality and CF3-Aryl Substituents on Secondary Structures of ß-Proline Tripeptides in Solution.

All possible variants of ß-proline functionalized tripeptides consisting of homo/hetero chiral monomeric all-cis 5-arylpyrrolidine-2,4-dicarboxylate units were synthesized for the first time by a nonpeptidic coupling method based on 1,3-dipolar cycloaddition chemistry of azomethine ylides. Secondary structures of ß-proline tripeptides in solution were determined using the NMR spectroscopy data. o-(Trifluoromethyl)phenyl substituent contributes to stereoselectivity of 1,3-dipolar cycloaddition and structural features of ß-proline tripeptides. A ß-proline CF3-tripeptide with alternating absolute chirality between adjacent pyrrolidine units mimics natural PPII helix secondary structure.

Crystal structure of 4-[(1R,2S,5R)-2-isopropyl-5-methyl-cyclo-hex-yl] 2-methyl (2S,4S,5R)-1-[(2S,3R,5R)-5-meth-oxy-carbonyl-2-(2-methyl-phen-yl)pyrrolidine-3-carbon-yl]-5-(2-methyl-phen-yl)pyrrolidine-2,4-di-carboxyl-ate.

The title compound, C38H50N2O7, represents a chiral ß-proline dipeptide. Corresponding stereogenic centres of constituting pyrrolidine units have opposite absolute configurations. The central amide fragment is planar within 0.1 Šand adopts a Z configuration along the N-CO bond. In the crystal, the hydrogen atoms of the methyl-ene groups form several short inter-molecular C-H⋯O contacts with the carbonyl oxygen atoms of an adjacent mol-ecule. The only active amino hydrogen atom is not involved in hydrogen bonding.

Control of Azomethine Cycloaddition Stereochemistry by CF3 Group: Structural Diversity of Fluorinated ß-Proline Dimers.

ß-Proline-functionalized dimers consisting of homochiral monomeric units were synthesized by a non-peptidic coupling method for the first time. The applied synthetic methodology is based on 1,3-dipolar cycloaddition chemistry of azomethine ylides and provides absolute control over the ß-proline backbone stereogenic centers. An o-(trifluoromethyl)phenyl substituent contributes to appropriate stabilization of the definite acrylamide chiral cis conformation and to achieve the dipole reactivity that is not observed for aryl groups lacking strong electronegative character.

Menthols as Chiral Auxiliaries for Asymmetric Cycloadditive Oligomerization: Syntheses and Studies of ß-Proline Hexamers.

To produce a novel class of structurally ordered poly-ß-prolines, an emergent method for synthesizing chiral ß-peptide molecular frameworks was developed based on 1,3-dipolar cycloaddition chemistry of azomethine ylides. Functionalized short ß-peptides with up to six monomeric residues were efficiently synthesized in homochiral forms using a cycloadditive oligomerization approach. X-ray, NMR, and CD structural analyses of the novel ß-peptides revealed secondary structure features that were generated primarily by Z/E-ß-peptide bond isomerism. Anticancer in cellulo activity of the new ß-peptides toward hormone-refractory prostate cancer cells was observed and was dependent on the absolute configuration of the stereogenic centers and the chain length of the ß-proline oligomers.