Laszlo Czollner

NEW KILOGRAM-SYNTHESIS OF THE ANTI-ALZHEIMER DRUG (-)-GALANTHAMINE

A concise, scalable synthesis of (−)-galanthamine, a drug being used for the treatment of Alzheimers disease, is described. The yield of the critical phenolic coupling step was optimized to 45–50%. For the reduction of the aryl bromide, air-activated LiAIH4 was used and racemic narwedine was converted to (−)-narwedine by a second order asymmetric transformation.

Synthesis of glycyrrhetinic acid derivatives for the treatment of metabolic diseases

The effect of glycyrrhetinic acid (GA) and GA-derivatives towards 11beta-hydroxysteroid dehydrogenase (11beta-HSD) was investigated. Novel compounds with modifications at positions C-3, C-11 and C-29 of the GA skeleton were prepared. Single crystal X-ray diffraction data of selected substances are reported and discussed.

Synthesis of new glycyrrhetinic acid derived ring A azepanone, 29-urea and 29-hydroxamic acid derivatives as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors

Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2. Whereas inhibition of 11β-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11β-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. Recently, we published a series of hydroxamic acid derivatives of glycyrrhetinic acid showing high selectivity for 11β-HSD2. The most potent and selective compound is active against human 11β-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11β-HSD1. Starting from the lead compounds glycyrrhetinic acid and the hydroxamic acid derivatives, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11β-HSD1 and 11β-HSD2 in cell lysates. Here we describe novel 29-urea- and 29-hydroxamic acid derivatives of glycyrrhetinic acid as well as derivatives with the Beckman rearrangement of the 3-oxime to a seven-membered ring, and the rearrangement of the C-ring from 11-keto-12-ene to 12-keto-9(11)-ene. The combination of modifications on different positions led to compounds comprising further improved selective inhibition of 11β-HSD2 in the lower nanomolar range with up to 3600-fold selectivity.

Enantiomeric resolution of galanthamine and related drugs used in anti-Alzheimer therapy by means of capillary zone electrophoresis employing derivatized cyclodextrin selectors

An analytical assay is presented for the determination of the enantiomeric composition of galanthamine and related synthetic and natural compounds. (-)-Galanthamine is isolated from Galanthus nivalis and is used in this optical pure form in the therapy of Alzheimers disease. Recent efforts for a total synthesis of unichiral (-)-galanthamine is connected with the need for a fast and reliable assay for the determination of the optical purity of the end product, as well as for optimizing and controlling the final steps in total synthesis particularly the asymmetric transformation of narwedine. In this paper the enantiomeric resolution of these compounds is reported employing a capillary electrophoretic system with beta-cyclodextrin derived chiral selectors. With the proposed system a number of galanthamine and narwedine derived analogous compounds could be separated, including 1-bromo- and N-alkyl-substituted compounds.

Synthesis of novel 3-amino and 29-hydroxamic acid derivatives of glycyrrhetinic acid as selective 11β-hydroxysteroid dehydrogenase 2 inhibitors.

Glycyrrhetinic acid, the metabolite of the natural product glycyrrhizin, is a well known nonselective inhibitor of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 1 and type 2. Whereas inhibition of 11β-HSD1 is currently under consideration for treatment of metabolic diseases, such as obesity and diabetes, 11β-HSD2 inhibitors may find therapeutic applications in chronic inflammatory diseases and certain forms of cancer. So far, no selective 11β-HSD2 inhibitor has been developed and neither animal studies nor clinical trials have been reported based on 11β-HSD2 inhibition. Starting from the lead compound glycyrrhetinic acid, novel triterpene type derivatives were synthesized and analyzed for their biological activity against overexpressed human 11β-HSD1 and 11β-HSD2 in cell lysates. Several hydroxamic acid derivatives showed high selectivity for 11β-HSD2. The most potent and selective compound is active against human 11β-HSD2 in the low nanomolar range with a 350-fold selectivity over human 11β-HSD1.

Efficient synthesis of glycyrrhetinic acid glycoside/glucuronide derivatives using silver zeolite as promoter

3-O-Glycopyranosides of glycyrrhetinic acid have been synthesized in good to high yields and excellent stereoselectivity using glycosyl bromide donors and silver zeolite as promoter. In addition to the preparation of glycosides containing beta-linked glucosyl, 2-deoxy-2-trichloroacetamido-glucosyl, galactosyl, cellobiosyl and lactosyl residues, also the deactivated acetylated methyl glucopyranosyluronate bromide donor could be coupled to triterpene aglycon ester derivatives in good yields. The ester protecting group located at C-30 of the oleanolic acid scaffold exerted an influence on the overall yield, with the methylester-protected glycosyl acceptor giving better yields compared to the allyl, benzyl as well as diphenylmethyl ester aglycon. The acetyl-protected glucuronides were differently deblocked in high yields via Zemplén deacetylation or via hydrogenolysis followed by Zemplén deacetylation, and alkaline hydrolysis, respectively, to allow for a selective liberation of the ester groups from either the glucuronide or the glycyrrhetinic acid unit, respectively. The target glycosides/glucuronides serve as probes for pharmaceutical studies aimed at defining structure-activity relationships of glycoside/glucuronide triterpenes.

Propargylaminyl 3α-hy-droxy-11-oxo-18β-olean-12-en-29-oate.

The title compound, C33H49NO3, is the propargylamide of 18β-glycyrrhetinic acid, a pentacyclic triterpenoid of interest as a therapeutic agent. The five six-membered rings of the glycyrrhetinic acid moiety show normal geometries, with four rings in chair conformations and the unsaturated ring C in a half-chair conformation. In the crystal, the terminal N-propargylcarboxamide group has remarkable structural effects on weak hydrogen-bond-like interactions. Particularly noteworthy are an intermolecular O—H⋯π interaction accepted side-on by the terminal alkyne group [O⋯C = 3.097 (2) and 3.356 (2) Å] and a short intermolecular C—H⋯O interaction [C⋯O = 3.115 (2) Å] donated by the alkyne C—H group. An N—H⋯O [N⋯O = 3.251 (2) Å] and a Calkyl—H⋯O [C⋯O = 3.254 (2) Å] interaction complement the crystal structure.

(+)-Methyl 3β-acet-oxy-13-carb-oxy-19-hy-droxy-11-oxo-C-norolean-18-en-30-oate γ-lactone.

The title compound, C33H46O7, is an unusual oxydation product of the therapeutic agent glycyrrhetinic acid that has, in comparison to the latter, a distinctly altered triterpene structure with one five- and four six-membered carbocycles complemented by a γ-lactone ring with a spiro-junction and a ring double bond. The junction between the five-membered ring C, a cyclopentanone ring, and the six-membered ring D, previously in question, was found to be cis, confirming earlier structure assignments based solely on chemical transformations. In the solid state, the compound exhibits five intra- and four intermolecular C—H⋯O interactions with H⋯O distances less than or equal to 2.70 Å and C—H⋯O greater than 100°.

(3β,18β,20β)-N-Eth­oxy­carbonyl­methyl-3-nitrato-11-oxoolean-12-ene-29-carboxamide methanol monosolvate

The title compound, C34H52N2O7·CH4O, is the methanol solvate of a difunctionalized derivative of the therapeutic agent 18β-glycyrrhetinic acid, a pentacyclic triterpene. The five six-membered rings of the glycyrrhetinic acid moiety show normal geometries, with four rings in chair conformations and the unsaturated ring in a half-chair conformation. This moiety is substituted by a nitrate ester group and an O-ethylglycine group. In the crystal, the nonsolvent molecules are packed parallel to (010) in a herringbone fashion with the nitrato, ethylglycine and methanol-O atom being proximate. The methanol solvent molecule is anchored via a donated O—H⋯Oacyl and an accepted N—H⋯O hydrogen bond, giving rise to infinite zigzag chains of hydrogen bonds parallel to [100]. Two weak intermolecular C—H⋯O interactions to the methanol and to an acyl oxygen establish links along [100] and [010], respectively.