Bozhana Mikhova

Alkaloids and Coumarins from Ruta graveolens

Summary. The aerial parts of Ruta graveolens cultivated in Bulgaria afforded four new 2-alkyl-4-(1H)-quinolone alkaloids together with thirteen known components. The new alkaloids were obtained as a mixture of homologues. The structures of all compounds were determined by spectroscopic methods.Zusammenfassung. Aus den oberirdischen Teilen von in Bulgarien gezogener Ruta graveolens konnten neben dreizehn bereits bekannten Substanzen vier neue 2-Alkyl-4(1H)-chinolonalkaloide als Gemisch homologer Verbindungen isoliert werden. Die Strukturen der neuen Komponenten wurden mit spektroskopischen Methoden aufgeklärt.

Isolation of triterpene saponins from Gypsophila capillaris

Four novel triterpenoid saponins have been isolated from Gypsophila capillaris. Three were monodesmosidic: 3 beta-hydroxyolean-12-en-23,28-dioic acid 28-O-[beta-D-glucopyranosyl-(1-->3)-beta-D-glucopyranosyl-(1-->2)] [beta-D-galactopyranosyl(1-->6)]beta-D-glucopyranoside, 3 beta-hydroxyolean-12-en-23-oxo-28-oic acid 28-O-[beta-D-glucopyranosyl-(1-->2)-beta-D-galactopyranosyl-(1-->3)] [beta-D-glucopyranosyl(1-->6)]beta-D-galactopyranoside, 3 beta-hydroxyolean-12-en-23,28-dioic acid 28-O-[beta-D-glucopyranosyl-(1-->2)-beta-D-galactopyranosyl-(1-->3)] [beta-D-glucopyranosyl(1-->6)]beta-D-galactopyranoside. The fourth was bisdesmosidic: 3 beta-hydroxyolean-12-en-23,28-dioic acid 23-O-beta-D-glucopyranosyl-28-O-[beta-D-glucopyranosyl-(1-->2)-beta-D- galactopyranosyl-(1-->3)][beta-D-glucopyranosyl-(1-->6)]beta-D- galactopyranoside. The structures of the compounds were elucidated by 1D and 2D NMR techniques and from other spectroscopic evidence.

Synthesis and cellular characterization of novel isoxazolo- and thiazolohydrazinylidene-chroman-2,4-diones on cancer and non-cancer cell growth and death

Coumarins are extensively studied anticoagulants that exert additional effects such as anticancerogenic and even anti-inflammatory. In order to find new drugs with anticancer activities, we report here the synthesis and the structural analysis of new coumarin derivatives which combine the coumarin core and five member heterocycles in hydrazinylidene-chroman-2,4-diones. The derivatives were prepared by derivatization of the appropriate heterocyclic amines which were used as electrophiles to attack the coumarin ring. The structures were characterized by spectroscopic techniques including IR, NMR, 2D-NMR and MS. These derivatives were further characterized especially in terms of a potential cytotoxic and apoptogenic effect in several cancer cell lines including the breast and prostate cancer cell lines MCF-7, MDA-MB-231, PC-3, LNCaP, and the monocytic leukemia cell line U937. Cell viability was determined after 48 h and 72 h of treatment with the novel compounds by MTT assay and the 50% inhibitory concentrations (EC50 values) were determined. Out of the 8 novel compounds screened for reduced cell viability, 4c, 4d and 4e were found to be the most promising and effective ones having EC50 values that were several fold reduced when compared to the reference substance 4-hydroxycoumarin. However, the effects were cancer cell line dependent. The breast cancer MDA-MB-231 cells, the prostate cancer LNCaP cells, and U937 cells were most sensitive, MCF-7 cells were less sensitive, and PC-3 cells were more resistant. Reduced cell viability was accompanied by increased apoptosis as shown by PARP-1 cleavage and reduced activity of the survival protein kinase Akt. In summary, this study has identified three novel coumarin derivatives that in comparison to 4-hydroxycoumarin have a higher efficiency to reduce cancer cell viability and trigger apoptosis and therefore may represent interesting novel drug candidates.

A secoiridoid glucoside and a phenolic compound from Fraxinus ornus bark

Abstract A new secoiridoid glucoside named ornoside and a new tyrosol derivative named ornosol have been isolated from Fraxinus ornus bark, along with the k

Epoxyconiferyl alcohol from Fraxinus oxycarpa bark

Abstract The new compound, epoxyconiferyl alcohol, has been isolated from the bark of Fraximus oxycarpa , along with the known hydroxycoumarins, esculin, fraxin, esculetin, isoscopoletin, fraxetin, and the secoiridoids, ligstroside and 10-hydroxyligstroside.

DFT–GIAO–NBO and 13C NMR study of the δ‐syn‐axial effect in 2,4‐disubstituted adamantanes

Six groups of diastereomeric 2,4‐disubstituted adamantanes were studied with DFT–GIAO–NBO (natural orbital analysis) methods. The calculated 13C chemical shifts reproduce well the experimental data. It was found that among all diastereomers, those bearing substituents in δ‐syn‐axial positions showed the largest overall deshielding, i.e. the sum of all 13C chemical shifts [Σδ(13C)] was the greatest and also had the highest delocalization contribution to the molecular energy evaluated with NBO. The higher delocalization energy is proposed to be the origin of the deshielding δ‐syn‐axial effect. Copyright

An improved synthesis of 4-chlorocoumarin-3-sulfonyl chloride and its reactions with different bidentate nucleophiles to give pyrido[1′, 2′:2,3]- and thiazino[3′,2′:2,3]-1,2,4-thiadiazino[6,5-c] benzopyran-6-one 7,7-dioxides

An improved synthetic method affording 4-chlorocoumarin-3-sulfonyl chloride (4) in very good yield (ca. 85%) is reported. This compound was reacted with various bidentate nucleophiles such as 2-aminopyridines and 2-aminothiazoles in order to obtain substituted pyrido- and thiazino-1,2,4-thiadiazino-benzopyranone dioxides (potential anticancer and anti-HIV agents). These reactions occurred rapidly at room temperature giving yellowish precipitates, which are insoluble in common organic solvents, making the purification process challenging. Further investigation has shown that these fused heterocycles are not stable and decompose with opening of the 1,2,4-thiadiazine ring.

A surprising eight-membered ring synthesis leading to enantiomerically pure tricyclic benzodiazepine derivatives

Abstract The synthesis of the title compounds 2 – 4 from naturally occurring ( R )-(+)-pulegone and o -phenylene diamines is described. Extensive NMR investigations prove that an eight-membered ring has been formed adopting a crown-type conformation.

Transformation of isogermacrone with lead tetraacetate: formation of a new cyclononane skeleton

Abstract The reaction of isogermacrone 2 with LTA under different conditions is described. In the presence of AcOH 2 undergoes mainly intramolecular cyclisation yielding theselinane-type products 4 - 6 . When MeOH is used as a solvent ring contraction occur predominantly affording the compounds 13 and 14 with a new cyclononane skeleton. The mechanism of the reactions is discussed.

NMReDATA, a standard to report the NMR assignment and parameters of organic compounds

Even though NMR has found countless applications in the field of small molecule characterization, there is no standard file format available for the NMR data relevant to structure characterization of small molecules. A new format is therefore introduced to associate the NMR parameters extracted from 1D and 2D spectra of organic compounds to the proposed chemical structure. These NMR parameters, which we shall call NMReDATA (for nuclear magnetic resonance extracted data), include chemical shift values, signal integrals, intensities, multiplicities, scalar coupling constants, lists of 2D correlations, relaxation times, and diffusion rates. The file format is an extension of the existing Structure Data Format, which is compatible with the commonly used MOL format. The association of an NMReDATA file with the raw and spectral data from which it originates constitutes an NMR record. This format is easily readable by humans and computers and provides a simple and efficient way for disseminating results of structural chemistry investigations, allowing automatic verification of published results, and for assisting the constitution of highly needed open‐source structural databases.