Ulrich Klar

New synthetic inhibitors of microtubule depolymerization

A new class of borneol esters that might be considered as biological analogs of paclitaxel regarding their action on microtubules has been found. By structure-activity optimizations, compounds stabilizing microtubules much better than paclitaxel while showing a remarkably reduced cytotoxic activity were obtained. This dissoziation will open completely new therapeutic areas.

11β-Aryl Steroids in the Androstene Series. The Role of the 11β-Region in Steroid Progesterone Receptor Interaction

Abstract The syntheses of 11β-arylandrost-4-en-3-one 24 and the corresponding 9β,19-cyclo derivative 8 are described. Steric interaction between C-19 and the aryl residue effects conformational changes of the steroid ring system that result in reduced affinity for the progesterone receptor. The conformation of 11β-arylandrostenes is discussed in comparison with known antiprogestational steroids.

Perfluorobutanesulfonyl fluoride — 1,8-diazabicyclo[5.4.0]undec-7-ene as a useful system in diol-epoxide transformation

Abstract The combination of n-perfluorobutanesulfonyl fluoride with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) proves to be a highly efficient system for the conversion of vicinal diols into epoxides, especially well-suited in demanding situations.

Novel prostanoid thromboxane A2 antagonists

Abstract The chemistry and in vitro pharmacology of novel prostanoid TXA 2 (TP)-receptor antagonists is described. (5Z)-(9R)-12-(4-Chlorobenzenesulfonamido)-9-fluoro-13,14,15,16,17,18,19,20-octanor-5-prostenoic acid was identified as a potent TP-receptor antagonist.

Synthesis of potent 6-oxo and 9-fluoro-PGE1-derivatives and their biological properties

Abstract The synthesis of the biologically potent 6-oxo-PGE 1 analog 18 and its 9-fluoro-derivative 21 as well as their biological data are presented.

HIGH STEREOSELECTIVITY IN THE WITTIG REACTION INDUCED BY THE INTERACTION OF CHARGES

Abstract The synthesis of carbacyclin analogues I based on the introduction of an α-chain to a suitable substituted bicyclo[3.3.0]octan-3-one derivative like 5 by a Wittig reaction leads generally to nearly 1:1-mixtures of E/Z-isomers. This lack of selectivity will change dramatically, if an acidic sulfonamide in the bicyclic framework is present. The observed Z-selectivity can be explained by an interaction of charges of the deprotonated sulfonamide and the electrophilic phosphorous atom in the Wittig reagent.

Novel prostanoid thromboxane A2 agonists

The chemistry and biology of novel TXA2(TP)-receptor agonists based on the prostanoid skeleton is described and structure-activity-relationships are discussed. One compound,(5Z,13E), (9R,15R)-9-fluoro-15-hydroxy-16-phenoxy-17,18,19,20-tetranor- 5,13-prostadienoic acid (33), was identified which is 10 times more potent than the standard TP-receptor against U 46619.

An attempt to synthesize prostanoid thromboxane A2 antagonists with an additional prostacyclin like quality

The preparation and biological characterisation of prostanoid TXA2(TP)-antagonists which are modified at position 9 to add a PGI2-like quality is described. Although we obtained highly potent TP-receptor antagonists, the synthesized compounds do not inhibit the ADP induced platelet aggregation and thus do not have any PGI2(IP)-mimetic properties.

Syntheses of new metabolically stabilized TXA2/PGH2-receptor antagonists and their biological properties

Abstract To enhance the metabolic stability of our TXA 2 /PGH 2 -receptor antagonists derived from the 2-oxabicyclo[2.2.1]heptane skeleton of the standard agonist U 46619, a synthesis was developed to introduce a 3-oxa moiety into the α-chain. The consequence of this structural modification on receptor binding and antiggregatory activity is discussed.

New TXA2/PGH2 receptor antagonists based on the carbacyclin skeleton

Abstract Syntheses of novel TXA2PGH2 receptor antagonists possessing the bicyclo[3.3.0]octane carbacyclin skeleton as described and structure activity relationships are discussed. It is shown that highly potent compounds can be obtained, when the lower prostanoid side chain is replaced by substituted aryl semicarbazones.