Structures and Evaluation of Biologically Active Constituents of "Cussonia Zimmermannii" Harms

For the present thesis 22 samples of seven African medicinal plants, the extracts of which had previously proved to possess an in vitro activity against T. b. rhodesiense and/or P. falciparum and 13 samples of six randomly selected plant species based on availability were collected in Tanzania. Of these 35 samples, 140 crude extracts were produced with four solvents of different polarity, and the extracts were tested for in vitro antitrypanosomal and antiplasmodial activity and for cytotoxicity. In addition the extracts were tested for the affinity to the GABAA receptor performed by radioligand binding experiments. Based on the considerable antitrypanosomal and antiplasmodial activity and the affinity to the GABAA receptor, two extracts were selected for bioassay-guided fractionation : the petroleum ether extract of the stembark of Commiphora fulvotomentosa Engl. because of its promising IC50 value of 2.1 mg/ml against T. b. rhodesiense and the high selectivity index of 21.4, and the petroleum ether extract of the rootbark of Cussonia zimmermannii Harms because of its IC50 value of 4.8 mg/ml against T. b. rhodesiense, its IC50 value of 3.3 mg/ml against P. falciparum, and the potent modulatory effect at the GABAA receptor of 151 %. After three fractionation steps the fractions of the petroleum ether extract of the stembark of Commiphora fulvotomentosa Engl. did not show any inhibitory activity against T. b. rhodesiense and were therefore not investigated further. Bioassay-guided fractionation of the petroleum ether extract of the rootbark of Cussonia zimmermannii Harms lead to the isolation of four polyacetylenes. By the application of MS, HR-MS, UV/VIS and IR methods and NMR experiments (1H-NMR, 13C-NMR, DEPT135, 1H-1H COSY, HMQC and HMBC) the structures of the four novel diynes were established : 8-Hydroxyheptadeca-4,6-diyn-3-yl acetate (MS-1 (25)), 8-Hydroxyheptadeca-1-ene-4,6-diyn-3-yl acetate (MS-2 (26)), 16-Acetoxy-11- hydroxyoctadeca-17-ene-12,14-diynyl acetate (MS-4 (27)), and 11,16-Diacetoxyoctadeca- 17-ene-12,14-diynyl acetate (MS-5 (28)). Additionally, stigmasterol (42) was isolated and identified by comparison of its spectroscopic data with those of an authentic sample. For the determination of the absolute configuration of MS-4 (27) at C(11) the Mosher method was used. The negative d values for the neighbouring protons suggested the S-configuration. But this result could not be confirmed by the 13C-NMR data since both positive and negative d values were obtained for the neighbouring carbons. Due to the fact, that the results for the protons and the carbons were not consistent the S-configuration for C(11) of MS-4 (27) could not be assigned with certainty. The isolated compounds MS-1 (25), MS-2 (26), and MS-4 (27) were tested for in vitro inhibitory activity against additional parasites like T. cruzi and L. donovani (axenic and in infected macrophages). 42 was not tested because it was a well known phytosterol which is ubiquitous in plants. Neither was MS-5 (28) tested, since the isolated amount was not sufficient. It was found that MS-1 (25) showed in all antiparasitic in vitro assays no higher inhibitory activity than the crude extract. MS-2 (26) showed promising activities in the T. cruzi and L. donovani (axenic and in infected macrophages) assay with IC50 values of 0.2, 0.039, and 0.098 mg/ml, respectively. The respective IC50 values of the standard drugs were 0.62, 0.18, and 0.29. The cytotoxicity was relatively high; therefore the selectivity with SI values of 18.0 and 36.7, respectively (T. cruzi, L. donovani in inf. mac.), was in a moderate range. MS-4 (27) showed also interesting activities in the T. cruzi and L. donovani (axenic) assays with IC50 values of 0.15 and 0.054 mg/ml. The SI value of 145.3 (T. cruzi) was high. Compared with the standard drugs the activities of MS-2 (26) and MS-4 (27) against T. b. rhodesiense and P. falciparum were in a moderate range. MS-1 (25), MS-2 (26), and MS-4 (27) were also tested in the GABAA receptor binding assay. Here MS-4 (27) showed the highest relative specific binding of 158 % at a concentration of 20 mg/ml, followed by MS-2 (26) with 152 % and MS-1 (25) with 138 %. In order to investigate whether the modulatory effect at the GABAA receptor leads to a chanel opening, the isolated compounds were investigated electrophysiologically. It was found that MS-1 (25), MS-2 (26), and MS-4 (27) act as potent positive allosteric modulators at GABAA receptors with a half maximal stimulation at a concentration of 0.6-3.5 mM and a maximal stimulation of 110-450 %. The compounds also showed unique subunit selectivity profiles, the stimulation was independend from the presence of the g subunit and resistant to the benzodiazepine antagonist Ro15-1788. These in vitro data suggested that MS-1 (25), MS-2 (26), and MS-4 (27) may be used to treat diseases of the central nervous system, specifically they may be used to treat states of anxiety, as sedatives/hypnotics, as muscle relaxants and as anticonvulsives (e.g. in epilepsy), and in the treatment of drug addiction. Therefore it was decided to patent the compounds for these indications [174]. All data are on the in vitro level. For a pharmaceutical application in vivo data are needed. Therefore MS-1 (25), MS-2 (26), and MS-4 (27) need to be synthesized in order to get more material for subsequent in vivo experiments

The synthesis and reactions of novel butadiyne derivatives

The synthesis, isolation and characterisation of aryl and heteroarylbutadiynes is herein reported. X-ray structural analysis for terminal butadiynes 72,118, 143, 157, 162 and 172 has been obtained. The packing diagrams indicate, in most cases, a hydrogen bonding interaction between the terminal acetylenie proton and the appropriate atom in the ring. An important feature of our synthetic methodology is the use of the 2-hydroxy-2-propyl protecting group, which facilitates purification from protected species, due to a large difference in polarity. The synthesis of mono- and di-deprotected bis-butadiynes is also reported; indeed X- ray structural analysis of di-deprotected pyridyl bis-butadiyne 234 has been obtained, as shown in the figure below The reactions of aryl and heteorarylbutadiynes and bis-butadiynes have also been investigated, leading to the synthesis of molecular-wire precursors 262 and 264

1,4-Bis[4-(tert-butyl­diphenyl­silyl)buta-1,3-diyn­yl]benzene

The title centrosymmetric mol­ecule, C46H42Si2, is composed of a central benzene ring with buta-1,3-diynyl chains at positions 1 and 4. These chains are terminated by tert-butyl­diphenyl­silyl groups, hence the molecule is dumbbell in shape. The mol­ecules are connected via C—H⋯π inter­actions in the structure, so forming an undulating two-dimensional network in the bc plane. There is also a weak π–π inter­action involving centrosymmetrically related phenyl rings with a centroid–centroid distance of 3.8359 (11) Å

FROM ACETYLENES TO METAL ACETYLIDE COMPLEXES: CARBON-RICH STRUCTURES FOR MOLECULAR ELECTRONICS

Electronics technology is moving so fast that an alternative for the “top-down” approach (lithography on silicon wafer) has to be found. Moore described in the now famous relationship the exponential growth of the number of transistors on a single chip that has become known as “Moore’s Law”, but this rate of progress has nearly reached its physical limits. As a chemist, the molecular scale is the smallest scale that can be manipulated in order to design more specific components. For this reason, the “bottom-up” approach is under rigorous investigation in chemistry and physics. Moreover, organometallic chemistry is increasingly employed for the synthesis of molecules for molecular electronics due to the versatile optoelectronic and structural properties offered by this class of compound (see section 1.5.). In this thesis, syntheses starting from simple but important carbon-rich organic building blocks to afford complex organometallic molecules are developed. The focus is on carbon-rich molecules such as oligoynes and oligo(phenyleneethynylene) derivatives due their high conjugation giving them good conduction properties. The preparation of oligoynes with trimethylsilylethynyl and pyridyl linkers and their preliminary single molecule conductivity data are presented in Chapter 2. In this work, a new, simple synthesis of the 1,10-bis(trimethylsilyl)penta-1,3,5,7,9-yne from cross-coupling reactions of 1,6-bis(triphenylphosphinegold)hexa-1,3,5-triyne with 1-iodo-2-trimethylsilylacetylene is developed, which was extended for the synthesis of oligoynes bearing pyridyl termini. “On complex” synthesis on Ru(II) butadiynyl molecules containing different aryl groups from electrodonating groups (-C6H4OMe-4; N,N-bis(4-methoxyphenyl)4-phenylamine), electroneutral (C6H4Me-4), anchoring groups (2,3-dihydrobenzo[b]thiophene (DHBT); C5H4N) to electrowithdrawing groups (C6H4CN-4) is discussed in Chapter 3. Moreover, elaboration and (spectro)electrochemistry of bimetallic complexes with oligoynes and arylyne bridges are reported and supported by DFT calculations. Oligo(phenyleneethynylene) metal complexes with various anchoring groups (pyridyl, thioanisole) and a different metal core (Pt and Ru) is explored in Chapter 4, in order to study the influence of the metal together with the linkers on the conductance. Single molecule conductance measurements and (spectro)electrochemistry together with DFT calculations are described. Finally, an investigation around the coordinating ligand, 2,2’:6’,2”-terpyridine (tpy), and opening new properties such as storage behaviour due to its specific geometry is discussed in Chapter 5. In this last chapter, the preparation of Ru(II) and Fe(II) tpy along with the electrochemical data are reported

a A convergent and modular synthesis of dienyl and diynyl isobutylamide natural products from echinacea and spilanthes herbal medicines

""Echinacea" and "Spilanthes" are popular over-the-counter herbal supplements derived from raw tissue or tissue extracts from plants such as Echinacea purpurea and Spilanthes acmella, respectively. Several chemical constituents have been identified as possible candidates for these plants' supposed medicinal activities, and include the "alkylamides," of which dienyl and diynyl analogs are prominent members. Isolation of these compounds from the plants is often difficult and results in poor yields. The goal of our research was to develop an encompassing synthesis scheme for dienyl and diynyl alkylamides (Figure 1) addressing consistent functional groups, using a Wittig reaction, a Horner-Wadsworth-Emmons reaction and a Sonogashira reaction. The total syntheses for these compounds are not novel, but have been known to be rather lengthy procedures. We are pleased to offer a novel synthesis that can synthesize a derivative of Spilanthol which involves only three reactions and well developed method for the diynyl structures using the Sonogashira coupling reaction."--Abstract from author supplied metadata

Synthesis, structure and electrochemistry of organometallic compounds bearing C(_n)N ligands

In this thesis, the synthesis of the organic cyanoacetylenes NCC≡CC(_6)H(_5) and NCC≡CC(_6)H(_4)-4-NMc(_2) and the metal cyanoacetylides Ru(C≡CC≡N)(PPh(_3))(_2)Cp, Ru(C≡CC≡N)(dppe)Cp* and Fe(C≡CC≡N)(dppe)Cp is presented and their coordination chemistry is explored. The structure and electrochemical behaviour of these novel cyano-carbon complexes is investigated and spectro-electrochemical methods are used to investigate the electronic structure of the cyanoacetylide compounds. In addition, in order to gain a greater understanding of the metal/ligand bonding interaction in these systems, the synthesis, structure and electrochemical behaviour of a series of metal nitriles [Ru(N≡CC(_6)H(_4)X)(PPh(_3))(_2)Cp][PF(_6)] (X = NO(_2), NMe(_2), CN) and [M(N≡CC(_6)H(_4)X)L(_2)Cp'][PF(_6)] (M = Ru, L = PPh(_3), Cp' = Cp; M = Ru, L2 = dppe, Cp' = Cp*; M = Fe, L(_2) = dppe, Cp' = Cp) were investigated, as were the complexes [{Ru(PPh(-3))(_2)Cp}(_2){μ-M(CN)(_4)}] (M = Ni, Pd, Pt) and [{Ru(dppe)Cp*}(_2){ μ - M(CN)(_4)}] (M = Ni, Pd , Pt), which feature a group 10 tetracyanometallate as a bridging moiety

Some reactions of azides with diynyl-bis(phosphine)ruthenium-cyclopentadienyl complexes

Abstract not availableMichael I. Bruce, Alexandre Burgun, Jonathan George, Brian K. Nicholson, Christian R. Parker, Brian W. Skelton, Nancy Scoleri, Christopher J. Sumby, Natasha N. Zaitsev

Angelica keiskei, an emerging medicinal herb with various bioactive constituents and biological activities.

Angelica keiskei (Miq.) Koidz. (Umbelliferae) has traditionally been used to treat dysuria, dyschezia, and dysgalactia as well as to restore vitality. Recently, the aerial parts of A. keiskei have been consumed as a health food. Various flavonoids, coumarins, phenolics, acetylenes, sesquiterpene, diterpene, and triterpenes were identified as the constituents of A. keiskei. The crude extracts and pure constituents were proven to inhibit tumor growth and ameliorate inflammation, obesity, diabetics, hypertension, and ulcer. The extract also showed anti-thrombotic, anti-oxidative, anti-hyperlipidemic, anti-viral, and anti-bacterial activities. This valuable herb needs to be further studied and developed not only to treat these human diseases but also to improve human health. Currently A. keiskei is commercialized as a health food and additives in health drinks. This article presents a comprehensive review of A. keiskei and its potential place in the improvement of human health

Synthesis of β-lactam fused enediynes by intramolecular kinugasa reaction: comparison of reactivity with monocyclic analogues

β-lactam fused enediynes have been successfully synthesized by intramolecular Kinugasa reaction in moderate yields. DSC studies indicated significant influence of the β-lactam ring upon the reactivity of enediynes. None of the β-lactam fused enediynes (under ring opening conditions) as well as the 11-membered monocyclic enediyne as the tosylate salt showed any cleavage of plasmid DNA. Interestingly, the 10-membered enediyne as the tosylate salt cleaved both single and double strands of plasmid DNA at micromolar concentration