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Atypical hemolytic uremic syndrome (aHUS) is a severe thrombotic microangiopathy characterized by uncontrolled complement activation against endothelial and blood cells. Mutations in the C-terminal target recognition domains 19-20 of complement regulator factor H (FH) are strongly associated with aHUS, but the mechanisms triggering disease onset have remained unresolved. Here we report that several aHUS-related mutations alter the binding of FH19-20 to proteins where lysines have reacted with malondialdehyde (MDA). Although FH19-20 did not interact with MDA-modified hexylamine, lysine-containing peptides, or a proteolytically degraded protein, it bound to MDA-modified polylysine. This suggests that FH19-20 recognizes only clustered MDA adducts. Binding of MDA-modified BSA to FH19-20 was ionic by nature, depended on positive residues of FH19-20, and competed with the polyanions heparin and DNA. This could not be explained with the mainly neutral adducts known to form in MDA modification. When positive charges of lysines were eliminated by acetic anhydride instead of MDA, the acetylated BSA started to bind FH19-20. Together, these results indicate that negative charges on the modified proteins dominate the interaction with FH19-20. This is beneficial for the physiological function of FH because by binding to the negative charges of the modified target, FH could prevent excess complement activation initiated by naturally occurring antibodies recognizing MDA epitopes with multiple different structures. We propose that oxidative stress leading to formation of MDA adducts is a common feature for triggers of aHUS and that failure of FH in protecting MDA-modified surfaces from complement activation is involved in the pathogenesis of the disease.

A novel microwave approach to the synthesis of tangutorine is described. The key steps comprise a diastereoselective aldol condensation of monoprotected glutaraldehyde and a microwave-assisted Pictet–Spengler reaction. The stereochemistry of the tangutorine diastereomers obtained was determined by means of NOE-experiments.

A practical and effective room temperature copper-catalyzed cyclization of Z-oximes is developed. 3-Methyl-1,2-benzisoxazoles are obtained in 58–79% yields. Also, the Z-selective synthesis of o-bromo acetophenone oximes is presented for the first time.

Six monoprotected acetals and -thioacetals of glutaradehyde and its symmetrical dimethyl derivatives were synthesized. Microwave-assisted heating proved to be a substantially more selective method for monoprotection than conventional heating. All reactions were efficient and only traces of diprotected material were formed.

For the first time, it has been shown that 2,6-dicyanopiperidines are formed in the Fry reaction via 1,4-dihydropyridine intermediates. A new synthetic approach for building 2,6-dicyanopiperidine derivatives by an extension of the sodium dithionite reduction of pyridinium salts is described. The stereochemistry of 2,6-dicyanopiperidine derivatives formed is discussed.

The ring system of the novel indole alkaloid tangutorine (1) has been synthesized via the Fry reaction. The final key steps were an oxidation/reduction procedure or alternatively, an epimerization sequence. Conformational and stereochemical aspects of the skeleton are discussed.

Direct addition of dimethyl malonate anion to a 1,4-conjugate iminium salt of 3-ethylindolo[2,3- a ]quinolizidine 4a (regenerated from the corresponding α-aminonitrile 4b ) afforded enamine 5. Catalytic hydrogenation of compound 5 led stereoselectively to compound 6 ( pseudo ), which is the highly desired intermediate for the preparation of several Corynanthe alkaloids, including (±)-hirsutine 7.

Preparation and determination of stereochemical properties of epimeric Z-geissoschizine and 19,20-dihydrogeissoschizine acetals arc described. The determination of the stereochemical properties is mainly based on nmr measurements.

The Claisen rearrangement of vinyl allyl ether 3 in refluxing toluene leads to a mixture of (±)- Z -geissoschizine 5 and (±)-15-epi- E -geissoschizine 6 [= (±)-3-epi- E -geissoschizine 6′], whereas vinyl allyl ether 4, under the same reaction conditions, affords only (±)-15-epi- Z -geissoschizine 15 [= (±)-3-epi- Z -geissoschizine 15′]. No (±)- E -geissoschizine 16 was formed. However, the formation of (±)-15-epi- E -geissoschizine 6 [ = (±)-3-epi- E -geissoschizine 6′], which has earlier been transformed to (±)- E -geissoschizine 16, represents a new, formal total synthesis of (±)- E -geissoschizine 16. A conformational study of the prepared compounds, mainly based on nmr measurements, is presented.

Syntheses are reported for isositsirikine isomers 1 – 6 and (16S*)-and (16R*)-17-deoxy- E -isositsirikines 9 and 10 (Model compounds 1,2 for the “synthetically missing” (16R)- and (16S)- E -isositsirikines 7 and 8 , respectively). Predominant conformations of the compounds, and of their C-16 configurations were determined on the basis of nmr measurements, especially NOE difference spectroscopy. The large difference in chemical shifts (δ 4.31 ppm versus δ 3.9 ppm), between the C-3-H-signals of (16R)- and (16S)- E -isositsirikines 7 and 8 is explained. The 13 C-nmr data confirm the non-identity of compounds 1 – 6 with rhazimanine and bhimberine, alkaloids isolated from Rhazya stricta .

Predominant conformations were determined for N a-Boc-deformyl- Z - and N a-Boc-deformyl- E -geissoschizines 1 and 2 and for their unprotected counterparts 3 and 4.

The affinity of strychnocarpine and related β-carbolines for serotonin, benzodiazepine, tryptamine, opiate and GABA receptors in rat brain was studied. Strychnocarpine showed a low to very low affinity for all the receptors tested. The weak binding to tryptamine receptors might explain part of the tremorigenic effects found earlier in the in vivo studies.

Short, stereoselective total syntheses for (±)-18,19-dihydrohunterburnine, (±) -10-O-methyl-18, 19-dihydrohunterburnine, (±)-10-hydroxycorynantheidol and (±)-10-methoxycorynantheidol are described.

A short and stereoselective synthesis for both dl -alloyohimbane and dl -epialloyohimbane using one and the same starting compound is presented.

Alkaline decarboalkoxylative cyclization of C(4)-monosubstituted 1-[2-(3-indolyl) ethyl-3methoxycarbonyl-1,4,5,6-tetrahydropyridines 1a and 1d leads mainly to C(2)-monosubstituted indolo[2,3- a quinolizidines 2a and 2d possessing the C(12b)H-C(2)H cis relationship [corresponding to the C(3)H-C(15)H cis relationship when the biogenetic numbering of indole alkaloids is used The C(5)-monosubstituted 1-[2-(3-indolyl) ethyl-3-methoxycarbonyl-1,4,5,6- tetrahydropyridine 1e yields almost exclusively C(3)-monosubstituted indolo[2,3- 3 quinolizidine 3e [C(12b)H-C(3)H trans relationship. In the case of the C(4),C(5)-disubstituted analogues 1f and 1g , the C(12b)H-C(2)H relationship is strongly influenced by the C(4)H-C(5)H relationship ( cis or trans ) of the original 1,4,5,6- tetrahydropyridine. Thus 1-[2-(3-indolyl)ethyl-3-methoxycarbonyl-4- methyl-5-ethyl-1,4,5,6-tetrahydropyridine 1f [C(4)H-C(5)H cis relationshipleads to 2-methyl-3-ethylindolo[2,3- a quinolizidines 1f and 1f [C(12b)H-C(2)H trans and cis relationships, respectively in about 98:2 ratio, whereas 1-[2-(3-indolyl)ethyl-3-methoxycarbonyl-4-methyl-5-ethyl-1,4,5,6-tetrahydropyridine 1g [C(4) H-C(5)H trans relationshipyields exclusively 2-methyl-3-ethylindolo[2,3- a quinolizidine 2g [C(12b)H-C(2)H cis relationship

The first total synthesis of the novel indole alkaloid, tangutorine 1 was performed in seven steps from 7,8-dihydroquinoline-5(6H)-one 2 .

A short, stereospecfic total synthesis of indole alkaloid (±)-corynantheidine 1 is described.

A new and interesting C(17)-functionalized desethyleburnamonine derivative 3 was synthesized. When subjected to different reducing conditions this dicarbonyl compound afforded compounds 4–7 .

A new route using very mild reaction conditions is described for the transformation of indoloquinolizidines 4 and 5 to the 1-oxo-1,2,3,4-tetrahydro-β-carbolines 2 and 3

Our recently developed method is successfully applied to the preparation of 1- and 3-monosubstituted 1,2,3,4,6,7,12,12b-octahydroindolo[2,3- a ]quinolizines possessing the C(12b)H-C(1)H and C(12b)H-C(3)H relationship, respectively, cis or trans at will. Complete 13C NMR data are presented for the prepared compounds.

The regioselectivity in the formation of different iminium species, generated from four indoloquinolizidines under the modified Polonovski reaction conditions, was studied using NaBD4-reduction and cyanide trapping of the intermediate iminium ions.

Beta-carbolines and indoloquinolizidines occur in plants, and some of the former compounds also in mammalian tissues. Many beta-carbolines cause tremor or convulsions, and they are among the most potent known endogenous compounds to bind to benzodiazepine, tryptamine and serotonin binding sites. In this study seven indoloquinolizidines which are formal derivatives of 1,2-disubstituted 1,2,3,4-tetrahydro-beta-carbolines were assayed for their affinity for benzodiazepine, tryptamine and serotonin binding sites in rat brain in vitro. Three of them exhibited significant affinity for tryptamine receptors: Ki values ranged from 0.97 microM upwards. The affinity spectra towards different receptors greatly varied from compound to compound showing selectivity to one or several of the binding sites now studied. These derivatives of beta-carbolines may be useful tools when assessing the physiological functions of the tryptamine and other binding sites.

Stereochemical control in the preparation of 2-substituted1,2,3,4,6,7,12,12b-octahydroindolo[2,3- a ]quinolizinespossessing at will the C(12b)H-C(2)H cis or trans configuration was achieved by catalytic reduction of the 2,3-dehydro analoques,which were either unsubstituted on the indole nitrogen orsubstituted with a BOC-group, respectively. The contribution ofdifferent conformations to the conformational equilibrium of theprepared compounds was estimated by 13C NMR spectral analysis.

Total synthesis of (±)-desmethylhexahydrovallesiachotaminelactones 1a and 1b , and their isomers 2a and 2b is described. The formation of other epimeric pairs of lactones ( 1a and 3a , and 1b and 3b ) from vallesiachotamine 4 is also described.

Six different lactams of the desethyleburnamonine-homoeburnamonine series were synthesized. Complete 13 C NMR data are presented for these compounds, as well as for their precursors. Special attention is paid to their C(20)–C(21) stereochemistry.

A practical synthetic entry to Wenkert's enamine 1 employing the modified Polonovski reaction is described. Complete 13C NMR spectral data of 1 is presented. Conformational analysis of the intermediate 1-hydroxy- and 1-ethyl-1-hydroxy-indoloquinolizidines 20a , 20b , 21a and 21b based on simple but reliable 13C NMR spectral correlations is presented.

The C(12b)-C(1)-C(2) stereochemical relationship in several racemic 1,2,3,4,6,7,12,12b-octahydroindolo [2,3-a]quinolizine derivatives has been determined by 13C NMR spectral analysis. The proper shift assignment was confirmed by recording the spectra of selectively deuterated derivatives. The C(12b)-C(1)-C(2) stereochemical relationship in indolo[2,3-a]quinolizines obtained either by alkaline decarboalkoxylative cyclization or by acid-induced cyclization of partially hydrogenated 1-[2-(3-indolyl)ethyl]-3-methoxycarbonylpyridine derivatives is discussed. The ambiguity existing in the preparation of dl-18,19-dihydroantirhine 2 by analogous decarboalkoxylative cyclization is considered.

The first successful preparations of the biochemically important isoquinuclidine ring system by the modified Polonovski reaction are described.

A new stereoselective three-step total synthesis of (±)-3- iso-19-epiajmalicine 4 starting from the easily accessible compound 1 is described.

Four monomeric indole alkaloids have been isolated from the bark of Rauvolfia media. Three of them are the known cabucine, reserpiline and mauiensine; the fourth is a new alkaloid, 12-hydroxymauiensine.