Oswald Lockhoff

New helicase-primase inhibitors as drug candidates for the treatment of herpes simplex disease

The vast majority of the world population is infected with at least one member of the human herpesvirus family. Herpes simplex virus (HSV) infections are the cause of cold sores and genital herpes as well as life-threatening or sight-impairing disease mainly in immunocompromized patients, pregnant women and newborns. Since the milestone development in the late 1970s of acyclovir (Zovirax), a nucleosidic inhibitor of the herpes DNA polymerase, no new non-nucleosidic anti-herpes drugs have been introduced. Here we report new inhibitors of the HSV helicase-primase with potent in vitro anti-herpes activity, a novel mechanism of action, a low resistance rate and superior efficacy against HSV in animal models. BAY 57-1293 (N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide), a well-tolerated member of this class of compounds, significantly reduces time to healing, prevents rebound of disease after cessation of treatment and, most importantly, reduces frequency and severity of recurrent disease. Thus, this class of drugs has significant potential for the treatment of HSV disease in humans, including those resistant to current medications.

An Access to Glycoconjugate Libraries through Multicomponent Reactions

Four-component reactions: The Ugi reaction of four suitably functionalized carbohydrate derivatives (as a per-O-benzylated amine, an aldehyde, a carboxylic acid, and an isocyanide) allow the effective assembly of diverse compound libraries. The complex glycoconjugates formed can be deprotected (see the picture for an example), and the resulting glycomimetics are of high interest for screening purposes.

Syntheses of glycosylamides as glycolipid analogs

Abstract In search of a simple synthetic access to analogs of naturally occurring glycolipids, glycosylamides have been synthesised in a two-step procedure from unprotected sugars, long-chain amines, and fatty acids. The N-glycosylation proceeded stereospecifically yielding crystalline β-glycopyranosylamines. 13 C NMR spectroscopy of the glycosylamines in organic solvents revealed partial anomerisation, leading to α-glycosylamines and in part to corresponding N -furanosides. Selective N-acylation of either pure β-glycosylamines or anomeric mixtures thereof with activated fatty acid led to formation of β-glycosylamides exclusively. As evidenced by NMR spectroscopy, the glycosylamides exhibited rotameric isomerism. The glycosylamides were found to be strong stimulators of the specific immune response against antigens.

Cripowellin A and B, a novel type of amaryllidaceae alkaloid from Crinum powellii

Abstract Two novel Amaryllidaceae alkaoids named cripowellin A (1) and B (3) were isolated from bulbs of Crinum powellii. Their structures were elucidated by spectroscopic investigations and confirmed by X-ray analysis.

Enantioselective synthesis of inositols as intermediates for the preparation of deoxy-inositol phosphates from D-galactose

Abstract Optically pure 6-deoxy-inososes, 6-deoxy-inositols and 6-deoxy-inositol-1,4,5-trisphosphates were synthesized from D-galactose by the carbohydrate-inosose Ferrier rearrangement. 6-Deoxy-inositolphosphates exhibit a tight binding to the Ins-P 3 -receptor making such compounds an interesting tool for studying the intracellular signalling. It is now well established that receptor stimulated hydrolysis of inositol phospholipids is a common mechanism for transmembrane signalling when cells respond to external stimuli such as hormones, neurotransmitters, antigens, light, growth factors and insulin 1 . It was also shown that phosphatidylinositol-4,5-bisphosphate [(Ptd)Ins(4,5)P 2 ] is a major inositol lipid hydrolysed by activated phospholipase C, resulting into the simultaneous generation of two “second messengers”, D- myo -inositol-1,4,5-trisphosphate [Ins(1,4,5)P 3 ] and diacylglycerol (DG) 2 . Ins(1,4,5)P 3 triggers the mobilization of Ca ++ from intracellular stores and DG stimulates protein phosphorylation via the activation of protein kinase C 3,4 . In addition (Ptd)Ins(4,5)P 2 contains a high percentage of arachidonic acid in the sn-2 position, which is released for lipoxygenase and cyclooxygenase pathways. These “second messengers” and their metabolites control and modulate vital physiological processes by their independent, additive and synergestic effects. 5 Therefore, it is conceivable that inhibitors of the key enzymes of the phosphoinositide cascade could be of medicinal interest and could be also useful tools to elucidate the individual role of the inositol metabolites in regulation of cell functions. 6,7 In view of difficulties in the isolation of inositol phosphate metabolites from natural sources and the need for structural analogues, several synthetic studies have been reported 8 . However, these have employed mostly the optically inactive myo inositol as a logical and cheap starting material. The crucial role of the phosphate esters at positions 1, 3, 4, and 5 of the myo inositol nucleus in the “second messengers” Ins(1,4,5)P 3 and Ins(1,3,4,5)P 4 is well established. For analogue synthesis, modifications of the centers C-1, C-3, C-4 and C-5 or alteration of the hydroxyl functions at neighboring carbons (C-2 or C-6), not involved at first glance in cellular processes, seemed justified. With these considerations in mind we have initiated a synthetic program aimed to proxide access to the hitherto unknown partially protected 6-deoxy-cyclitols 8 and 9, appropriate precursors of a variety of chiral deoxy-inositol phosphates 9 . Our approach to the deoxy-inositols 8 and 9 has been envisaged from the chiral deoxy-inososes 6 and 7 which could be obtained by mercury(II) mediated carbohydrate-inosose Ferrier rearrangement 10 from hex-5- ene -pyranoside 5. Olefin 5 was readily prepared in a four steps sequence from methyl-β-D-galactopyranoside 1 in 60% overall yield 11 . Treatment of 1 with 1,1-dimethoxycyclohexane in DMF in presence of sulfuric acid afforded acetal 2 in 90% yield. The latter was selectively brominated with triphenylphosphine-carbontetrabromide, leading to 3 (m.p. 122–123°C). Benzylation of 3 by a phase transfer process (powdered KOH, benzyltriethylammonium chloride, benzyl bromide in CH 2 Cl 2 ) furnished benzyl ether 4 (m.p. 94–95°C,[ α ] rmD 20 + 46). Access to olefin 5 (m.p. 61–62°C, [ α ] rmD 20 − 55) was achieved by two methods. Initially the bromo compound 4 was dehydrobrominated with sodium hydride in DMF (3h, 100°C) giving 5 in 90% yield 12. An alternative route for the

Glycoconjugate Libraries Accessed by Multicomponent Reactions

Glycobiology opens a wide field for new therapeutic approaches. However, the complexity and unavailability of various carbohydrate test compounds has excluded this class of natural products from modern screening systems. Alternatively, glycomimetics are considered to be more drug-like candidates for development. By means of multicomponent condensations (MCCs) utilizing suitable carbohydrate synthons, rapid and effective access to glycoconjugate libraries can be obtained. The flexibility of MCCs allows the assembly of diverse carbohydrate containing libraries. It may be assumed that MCCs containing carbohydrate moieties will play an important role in glycomimetic chemistry and biology.

Structural and dielectric properties of synthetic glycolipids in mixtures with water

Three synthetically produced glycolipids, N-(beta-D-glucopyranosyl)-N-octadecyl-stearoylamide (OSGA), N-(beta-D-glucopyranosyl-N-octadecyl-oleoylamide (OOGA), N-(beta-D-galactopyranosyl)-N-octadecyl-lauroylamide (OLGA) have been studied in different mixtures with water by x-ray diffraction and dielectric measurements with microwaves at 9.4 GHz. The measurements were performed in the temperature range -50-70 degrees C. X-Ray diffraction revealed a direct L(beta) --> H( parallel) transition at 20 degrees C, 60 degrees C, and 45 degrees C depending on the glycolipid species but nearly not on the water content. The hexagonal phases are saturated at a water content of approximately 20 wt%. The lamellar phase absorbs even less water (< 10 wt%). The dielectric data show that in the H( parallel) phase the binding of water is stronger than in the L(beta) phase. In the temperature range below 0 degrees C, OSGA and OOGA show a subzero transition due to the freeze-out of water in a separate ice phase. This transition can be seen in an abrupt decrease of the dielectric function because the dielectric response of ice is much smaller at microwave frequencies. OLGA does not show the subzero transition but an additional transition, hexagonal --> distorted hexagonal at 60 degrees C.

Syntheses of Peptidoglycolipid Analogs with Distinct Immunomodulating Activities

ABSTRACT Amphiphilic 2-amino-2-deoxy-β-D-glucopyranosylamides were synthesized from N-protected glucosamine derivatives via N-glycosidation with fatty amines, subsequent N-acylation with fatty acid derivatives and deprotection. They could further be modified with amino acids to give peptido-glycopyranosyl amides, some of which exhibited strong immunostimulatory (BAY Q8939, 8) or immunoadjuvant (BAY R1005, 9) activities.

Synthese eines antibiotisch aktiven disaccharids

Abstract The aminodisaccharide glycoside methyl 2,4-diamino-2,4-dideoxy-6- O -(2,6-diamino-2,6-dideoxy-α- d -glucopyranosyl)-β- d -glucopyranoside ( 4 ), which exhibits a structural resemblance to neamine, was synthesized via the azido method. Starting from 6- O -acetyl-2-azido-3,4-di- O -benzyl-2-deoxy-α- d -glucopyranosyl bromide, the α- d -glycosylation of O-6 of methyl 2,4-diazido-3- O -benzyl-2,4-dideoxy-β- d -glucopyranoside was accomplished stereoselectively at low temperatures in the presence of mercury bromide. Against some gram-negative test-organisms, the activity of 4 was found to be in the same range as neamine, but directed against different germs.