Dieter Hamprecht

The antimicrobial natural product chuangxinmycin and some synthetic analogues are potent and selective inhibitors of bacterial tryptophanyl tRNA synthetase.

The antimicrobial natural product chuangxinmycin has been found to be a potent and selective inhibitor of bacterial tryptophanyl tRNA synthetase (WRS). A number of analogues have been synthesised. The interaction with WRS appears to be highly constrained, as only sterically smaller analogues afforded significant inhibition. The only analogue to show inhibition comparable to chuangxinmycin also had antibacterial activity. WRS inhibition may contribute to the antibacterial action of chuangxinmycin.

1,2,4-Triazolyl Azabicyclo[3.1.0]hexanes: A New Series of Potent and Selective Dopamine D3 Receptor Antagonists

The discovery of new highly potent and selective dopamine (DA) D(3) receptor antagonists has recently allowed the characterization of the DA D(3) receptor in a range of preclinical animal models of drug addiction. A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes, members of which showed a high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles, is reported here. Members of a group of derivatives from this series showed good oral bioavailability and brain penetration and very high in vitro affinity and selectivity for the DA D(3) receptor, as well as high in vitro potency for antagonism at this receptor. Several members of this series also significantly attenuate the expression of conditioned place preference (CPP) to nicotine and cocaine.

Potent synthetic inhibitors of tyrosyl tRNA synthetase derived from C-pyranosyl analogues of SB-219383.

Novel pyranosyl analogues of SB-219383 have been synthesised to elucidate the structure-activity relationships around the pyran ring. Analogues with highly potent stereoselective and bacterioselective inhibition of bacterial tyrosyl tRNA synthetase have been identified. A major reduction in the overall polarity of the molecule can be tolerated without loss of the nanomolar level of inhibition.

Inhibitors of bacterial tyrosyl tRNA synthetase: synthesis of four stereoisomeric analogues of the natural product SB-219383.

Synthetic analogues of the microbial metabolite SB-219383 have been synthesised with defined stereochemistry. Densely functionalised hydroxylamine containing amino acids were prepared by the addition of a glycine anion equivalent to sugar-derived cyclic nitrones. One of four stereoisomeric dipeptides incorporating these novel amino acids was found to be a potent and selective inhibitor of bacterial tyrosyl tRNA synthetase, suggesting analogous stereochemistry of the natural product.

New fused benzazepine as selective D3 receptor antagonists. Synthesis and biological evaluation. Part one : [h]-fused tricyclic systems

The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The introduction of a tricyclic [h]-fused benzazepine moiety on the recently disclosed scaffold of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines is reported. A full rat pharmacokinetic characterization is also reported.

Optically active 2H-azepines: Synthesis and rearrangement into their 3H-isomers

Abstract A general synthesis of optically active 2H-azepines 12 starting from α-amino acids is described. The 2H-azepines easily rearrange into the corresponding 3H-isomers 18. The pungent taste of chalciporone (1) and simple 2,7-dialkylsubstituted 2H-azepines is due to the 2H-azepine nucleus and is independent of the absolute configuration at C-2.

New fused benzazepine as selective D3 receptor antagonists. Synthesis and biological evaluation. Part 2 : [g]-Fused and hetero-fused systems

The synthesis and the SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The new scaffolds of the [g]-fused and the hetero-fused tricyclic benzazepine are here reported together with their pharmacokinetic profile.

The identification of a selective dopamine D2 partial agonist, D3 antagonist displaying high levels of brain exposure.

The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.

ASSEMBLY OF THE ANTIFUNGAL AGENT FR-900848 AND THE CETP INHIBITOR U-106305: STUDIES ON REMARKABLE MULTICYCLOPROPANE NATURAL PRODUCTS

The full structural elucidation of FR-900848, an antifungal pentacyclopropane nucleoside natural product from Streptoverticillum fervens, is reported. A series of model compounds are prepared using multiple asymmetric Simmons–Smith cyclopropanation reactions. Comparisons of spectroscopic data of synthetic 1,2-dicyclopropylethene, quatercyclopropane-2,2′′′-dimethanol and 2-methylcyclo-propanecarbaldehyde derivatives of defined absolute stereochemistry with FR-900848 and its degradation products are used to unequivocally establish the absolute stereochemistry of the natural product. A C 2 -symmetric quatercyclopropane-2,2′′′-dimethanol is converted by a sequence of desymmetrisation, selective monocyclopropanation of a 5-(quatercyclopropyl)penta-2,4-dien-1-ol derivative, deoxygenation and Horner–Emmons homologation into the fatty acid side chain ofFR-900848. Coupling of this carboxylic acid with 5′-amino-5′-deoxy-5,6-dihydrouridine gives synthetic FR-900848. The unusual helical structure of FR-900848 is discussed and compared with U-106305, a cholesteryl ester transfer protein inhibitor from the fermentation broth of Streptomyces sp. UC 11136. The full structure and stereochemistry of U-106305 is established by total synthesis using a bidirectional strategy closely following the route to FR-900848.

RECENT ADVANCES IN THE SYNTHESIS OF ANTIFUNGAL AGENTS

FR-900848 is a pentacyclopropane nucleoside antifungal agent isolated from the fermentation broth of Streptoverricillium fervens. The full structure with relative and absolute stereochemistry of this unusual natural product were established by a combination of partial synthesis qd degradation. This assignment was confirmed by total synthesis from (E,E)-2,4-hexadiene- 1,6-diol using three sequential asymmetric cyclopropanation reactions, Homer Emmons homologation and selective deoxygenation.