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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.

Aldols from aliphatic aldehydes had been synthesized enantioselectively using Singh’s catalyst. Self and crossed aldol reactions with several linear aldehydes were performed.

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.

As part of continuous search for new chelating agents for transition metal ions, a practical method for the preparation of hydroxybenzyl derivatives of diethylenetriaminepentaacetic acid (DTPA) has been developed in this study. N,N″-bis(2-hydroxybenzyl)diethylenetriamine-N,N′,N″-triacetic acid (HBDTTA) and four other hydroxybenzyl derivatives of DTPA have been synthesized. The structures and chelating capacity of three ligands with Fe3+ have been predicted using density functional theory-based calculations at the BP86/TZVP level within a previously developed and tested computational procedure. The results show that like DTPA, HBDTTA can adopt several different six- and seven-coordinate complex structures. The good stability of Fe3+ complexes of two HBDTTA derivatives indicates that HBDTTA-type ligands can be modified by removing some of their functional groups without greatly affecting their metal-binding efficiency.

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 total syntheses of 11-methoxydeethyleburnamonines (4) and (13) were carried out with use of 6-methoxytryptophyl bromide (5) as starting material. Compound 5 was converted in three steps to trans-ester 8. Acid-catalysed epimerization of 8, lithium aluminum hydride reduction of the ester group, tosylation and substitution with cyanide gave the cis-nitrile 12. Acid-induced cyclization of 12 yielded mainly (±)-trans-11-methoxydeethyleburnamonine (13), whereas base-induced cyclization gave (±)-cis-11-methoxydeethyleburnamonine (4).

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.

10-Methoxydihydrocorynantheol and 10-methoxycorynantheidol were synthesized from 5-methoxytryptophol and 3-acetylpyridine. (13)C-NMR data of the prepared compounds and their synthetic intermediates are given.

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 HPLC enantiomeric separation of racemic indole alkaloids tacamonine, 17α-hydroxytacamonine, deethyleburnamonine, and vindeburnol was accomplished using Chiralpak AD and Chiralcel OD as chiral stationary phases. Small structural differences affect the enantioselectivity ability of these phases. Single enantiomers of tacamonine and vindeburnol were isolated by semipreparative HPLC and their CD spectra and optical rotations were measured. Chirality 13:691–693, 2001. © 2001 Wiley-Liss, Inc.

The title synthesis involves a general method which permits the preparation of 1-,2- and 3- substituted 1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizine derivatives possessing the C(12b)H-C(1)H , C(12b)H-C(2)H and C(12b)H-C(3)H relationship (corresponding to the C(3)H-C(15)H and C(3)H-C(20)H relationship,respectively, when the biogenetic numbering of indole alkaloids is used) cis or trans at will.

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.

Cleavage of the C-20 ethylidene side-chain of deformyl-Z-geissoschizine (1) and deformyl-E-geissoschizine (2), and their N a -Boc derivatives (11) and (12), utilizing the modified Polonovski reaction, is described. Mechanistic considerations are presented

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

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.

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.

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

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

1H- and 13 C-NMR spectral data are presented for six p-terphenylquinone derivatives 3-8 (and for two monosubstituted quinones 1 and 2, used as model compounds) and for 9,10-phenanthraquinone (9) and retenequinone (10). The chemical shifts were confirmed through correlation spectroscopy and NOE measurements.

1H- and 13C-NMR spectral data are presented for ajmaline (1), 17-O-acetylajmaline (2), isoajmaline (3), isosandwichine (4), rauflorine (5), vincamajine (6), and vincamedine (7). Some corrections to the previously reported assignments of compound 6 (1H-NMR) and compounds 3, 4 and 7 (13C-NMR) have been made. The 13C-NMR chemical shifts for rauflorine 5 are presented for the first time.

The first total synthesis of racemic tangutorine, a novel indole alkaloid, was performed in 7 steps. The key reactions, dithionite reduction and acidic cyclization provided easy access with good yields to the tangutorine skeleton. Comprehensive NMR spectroscopic data of new compounds are given. Chiral HPLC separation of enantiomers is reported.

The 13C NMR spectra of thirteen methoxycarbonylpyridine derivatives and two pyridine lactones are interpreted. The substituent increments for the methoxycarbonyl group in 2-, 3- and 4-substituted pyridines are reported.

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