Martin Hein

Liquid crystals based on fluorinated carbohydrates

Fluorine introduced in the hydrophilic or the hydrophobic region of amphiphiles influences the thermomesomorphy of amphiphilic and monophilic fluorosugars in a very specific manner. This paper is the first review about chiral mesogens based on fluorinated carbohydrates. It covers the literature published so far. Analytical objectives are given to: (i) Effects of fluorine atoms on the H-bonding network of the hydrophilic region of sugar amphiphiles; (ii) Effects of perfluoroalkyl chains compared to alkyl chains; (iii) Polymorphism, e.g., also formation of smectic S(C)* phases.

Sensitization of melanoma cells for death ligand-induced apoptosis by an indirubin derivative—Enhancement of both extrinsic and intrinsic apoptosis pathways

Until today effective therapies are lacking for metastatic melanoma. The death ligand TRAIL appears as promising in cancer treatment; however, melanoma cells reveal both preexisting and inducible TRAIL resistance. Here, we present evidence that the recently described indirubin derivative 8-Rha-β enhances melanoma cell sensitivity for death ligands and overcomes resistance to TRAIL and CD95 agonists. Indirubin is known from traditional Chinese medicine and is a potent kinase inhibitor. Unraveling of apoptotic signaling pathways revealed that TRAIL resulted in a quick (within 8h) downregulation of both agonistic TRAIL receptors DR4 and DR5, in a kind of negative feed-back loop. Treatment with indirubin, however, mediated upregulation of both receptors, thus compensating this negative feed-back loop by TRAIL. Furthermore, indirubin activated intrinsic apoptosis pathways, seen in loss of mitochondrial membrane potential and release of cytochrome c. The mitochondrial response appeared as related to upregulation of Bax and Bad and to downregulation of Mcl-1. Remarkably, indirubin in combination with TRAIL was also able to overcome apoptosis resistance due to ectopic Bcl-2 overexpression. The tumor suppressor p53 appeared as master regulator of these propapoptotic changes and is the transactivator of proapoptotic proteins which was upregulated by indirubin. Taking into account the physiological role of death ligands in immune surveillance, sensitization of melanoma cells for death ligands may be supportive for an anti-tumor immune response. Furthermore, combinations with kinase inhibitors, such as indirubin 8-Rha-β may help for a breakthrough of TRAIL-mediated strategies in melanoma.

NMR spectra of fluorinated carbohydrates.

Recent advances in structural and conformational analysis of fluorinated carbohydrates by NMR spectroscopy are reviewed. Characteristic 1H, 13C, and 19F NMR chemical shifts and coupling constants for selected examples are given and the spectral data of a series of fluorinated carbohydrates were collected in continuation of the review of Csuk and Glänzer [Adv. Carbohydr. Chem. Biochem., 46 (1988) 73-177].

A NEW GROUP OF LIQUID CRYSTALS BASED ON PERFLUOROALKYLATED CARBOHYDRATES

The mesogenic fluoroalkyl β-d-glucopyranosides 5a-d (smectic A) were generated via a dithionite initiated addition of the homologous 1-iodo-perfluoroalkanes 1a-d to allyl 2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (2) forming 3a-d followed by hydrodeiodination to 4a-d and deacetylation.

Synthesis and Bioactivity of Carbohydrate Derivatives of Indigo, Its Isomers and Heteroanalogues

have been used for a long time. They have technical applications, and are of considerable theoretical interest as well. The pigment can be obtained from various higher plants and fungi such as Baphicacanthus cusia (Acanthaceae), Calanthe veratrifolia (Orchidaceae), Isatis tinctoria (Brassicaceae), Polygonum tinctorium (Polygonaceae), Schizophyllum commune, and Agaricus campester through a process that involves its formation from precursors such as indican and isatan. Numerous derivatives of indigo have also been synthesized for commercial purposes. Until 2002, only three naturally occurring substituted indigos were known: the well-known Tyrian purple (isolated from purple snail) and two other brominated indigos. In 2002, Laatsch et al. reported the isolation of the akashines A, B, and C from terrestric Streptomyces spp. (Figure 2). Besides the 5,5’-dichloro-substituted indigo moiety, the akashines contain an N-glycosidic 4-amino-4,6-didesoxyglucose (akashine A) or a 4-acetamido-4,6-didesoxyglucose moiety (akashine B). They exhibit considerable growth inhibitory activity toward various human tumor cell lines, in contrast to the pharmacologically inactive non-glycosylated indigo. Indirubin, the red isomer of indigo, is the active ingredient of the traditional Chinese medicinal recipe Danggui Longhui Wan, which has been used for the treatment of myelocytic leukemia. This substance and its substituted derivatives are potent inhibitors of several kinases such as glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinases (CDKs). 9] Phosphorylation of serine, threonine, and tyrosine residues by cellular protein kinases plays an important role in the regulation of various cellular processes. Protein kinases constitute the largest family of human enzymes and are considered to be the largest class amenable to therapeutic intervention by smallmolecule drugs. CDKs and GSK-3 play key roles in a large number of cellular processes. They are involved in various diseases, including certain cancers, Alzheimer’s disease, Parkinson’s disease, and cardiovascular diseases, inflammation, and AIDS among others. 13] Both families of kinases have been used extensively as targets to identify small-molecular-weight pharmaceutical inhibitors of potential therapeutic interest. Among these inhibitors, the bis-indole indirubin and its analogues have gathered considerable attention, as they were discovered to inhibit CDKs and GSK-3. For example, 5-substituted indirubins display high inhibitory potency toward various CDKs and GSK-3b. 9, 14] Among indirubin isomers isolated from marine organisms, the natural product 6-bromoindirubin and its synthetic, more cell-permeable derivative 6-bromoindirubin3’-oxime also show enhanced selective inhibition of GSK-3 versus CDKs. 16] The high inhibitory potency of 5-nitroindirubin-3’-oxime led various research groups to synthesize disubstituted indirubins, namely at positions 5 and 7, thereby possibly combining selectivity and high activity. Moreover, the Figure 1. Indigo and its isomers. Figure 2. Akashin A.

Amphipilic and mesogenic carbohydrates XII. New thermotropic mesogens based on perfluoroalkyl-substituted carbohydrates

In continuing studies of amphiphilic and mesogenic carbohydrates, the mesomorphic properties of a new group of perfluoroalkylated amphiphilic mesogens are discussed. Smectic A phases dominate the mesomorphic behaviour of the new materials, but one compound exhibits a columnar mesophase and three others have SmA-SmC* transitions. The synthesis of these materials has already been reported and involved dithionite-mediated O- and S-perfluoroalkylations with 1-iodoperfluoroalkanes.

Organofluorine compounds and fluorinating agents. Part 25. Dithionite mediated C- and S-perfluoroalkylations of monosaccharide derivatives

Abstract Allyl 2,3,4,6-tetra-O-acetyl-β- d -glucoside (1), 2,3,4,6-tetra-O-acetyl-1-thio- d -glucopyranose (6), and 2,3,4,6-tetra-O-acetyl-1-thio- d -galactopyranose (9) were alkylated with 1-iodo-perfluoroalkanes (C4F9I, C6F13I, C8F17I, C10F21I) giving the corresponding (2-iodo-3-perfluoroalkyl-propyl) glucosides 2a–d, perfluoroalkyl s- d -thioglucosides 7b,c, and perfluoroalkyl s- d -thiogalactosides 10a-c, respectively. From these compounds the amphiphilic sugars 4a–d, 8b,c, and 11b,c were synthesized. The deacetylation of 3a–d, 7b,c, and 10b,c was carried out by treatment with alumina-supported CsF. Finally, 4c was converted to 5 by a regioselective 6-O-decanoylation. The “single tailed” amphiphiles 4a–d, 8b,c, and 11b,c are liquid crystals (SA-type), whereas compound 5, which contains a lipophilic as well as a fluorophilic chain, forms a columnar mesophase.

Synthesis and antiproliferative activity of selenoindirubins and selenoindirubin-N-glycosides

Selenoindirubins and selenoindirubin-N-glycosides were prepared by the reaction of isatins and isatin-N-glycosides with 3-acetoxy-benzo[b]selenophene, respectively. While selenoindirubin-N-glycosides have not been reported before, three non-glycosylated selenoindirubins were previously reported, but without quantities, yields, scales, experimental details and spectroscopic data. In addition, the work could, in our hands, not be reproduced to prepare pure products. The present paper includes an optimized procedure for the synthesis of selenoindirubins and their complete characterization. Both selenoindirubins and selenoindirubin-N-glycosides showed antiproliferative activity in lung cancer cell lines. In melanoma cells, antiproliferative effects were further accompanied by induced apoptosis in combination with the death ligand TRAIL.

Synthesis of 6H-indolo[2,3-b]quinoxaline-N-glycosides and their cytotoxic activity against human ceratinocytes (HaCaT)

N-glycosides of 6H-indolo[2,3-b]quinoxalines were prepared and structurally characterized. The synthesis relies on the cyclocondensation of isatine-N-glycosides with 1,2-diaminobenzenes. Some products exhibit weak cytotoxic activity against human ceratinocytes (HaCaT).

Synthesis of Thia-Analogous Indirubin N-Glycosides and their Influence on Melanoma Cell Growth and Apoptosis

Glycosylated indoles possess remarkable pharmacological activity against different malignant tumor cells. Prominent derivatives with antitumor activity include the natural products staurosporine, K-252d, rebeccamycin and tjipanazoles. Indigo, indirubin, and isoindigo contain a bis-indole framework and are found in a number of natural products. We previously reported the synthesis of indigo-N-glycosides (blue sugars). This type of core structure is present in the akashines A–C, which were isolated by Laatsch et al. from Streptomyces sp. GW48/1497. In contrast to the inactive parent indigo, the akashines show a remarkable antitumor activity against various human cancer cell lines. Indirubin, the red isomer of indigo, is the active ingredient in the traditional Chinese medicinal recipe Danggui Longhui Wan, which has been used for the treatment of myelocytic leukemia. This substance and its substituted derivatives are potent inhibitors of several kinases involved in intracellular signaling pathways, such as GSK-3b and cyclin dependent kinases (CDKs). Recently, we reported the synthesis of indirubin-Nglycosides (red sugars), which showed considerable antiproliferative activity against various human cancer cell lines. Sassatelli et al. described the preparation of isoindigo-N-glycosides, which also possess considerable antiproliferative activity and kinase inhibitory potency. Notably, both the deprotected and protected isoindigo-N-glycosides are of pharmacological relevance. For example, the biological activity of ‘Natura‘, acetylprotected b-d-xylopyranosyl-N-isoindigo, was reported to be higher than the activity of its deprotected analogue. Herein, we report the first synthesis of thia-analogues of indirubin-Nglycosides and their influence on melanoma cell growth, apoptosis and intracellular signaling. Compounds with a reactive methylene group like indoxyl, 3coumaranone or thiaindane-3-one are known to give condensation products with isatin, where only the reactive b-carbonyl group of the isatin is involved in the reaction. N-Glycosylated isatins are also suitable for such condensation reactions. 8] As starting materials in the synthesis of thia-analogous indirubinN-glycosides, we used isatin-N-glycosides with different carbohydrate moieties and thiaindane-3-one. In the case of the sugar l-rhamnose, acetyl-protected N-(b-l-rhamnopyranosyl)isatin (4-Rha-b) was prepared from the acetyl-protected aniline-N-rhamnoside (3-Rha-a,b), which was obtained by reaction of l-rhamnose with aniline and subsequent acetylation (Scheme 1). 10] Furthermore, the corresponding isatin-b-N-glycosides of d-mannose, d-glucose and d-galactose were prepared under similar conditions. Thiaindane-3-one was prepared from thiosalicylic acid and ethyl acetoacetate in the presence of sulfuric acid according to a procedure published by Friedl nder. Reaction of the acetyl-protected isatin-N-glycosides (4-b) with thiaindane-3-one under mildly acidic conditions resulted in the formation of thia-analogous indirubin-N-glycosides in good to very good yields (see example given in Scheme 2).