Grzegorz Grynkiewicz

Synthesis of alkyl 4,6-di-o-acetyl-2,3-dideoxy-α-d-threo-hex-2- enopyranosides from 3,4,6-tri-o-acetyl-1,5-anhydro-2-deoxy- d-lyxo-hex-1-enitol (3,4,6-tri-o-acetyl-d-galactal)

Abstract 3,4,6-Tri- O -acetyl- d -galactal, on treatment in 1,2-dichloroethane with alcohols and stannic chloride as catalyst, readily undergoes allylic rearrangement-substitution, forming alkyl 4,6-di- O -acetyl-2,3-dideoxy-α- d - threo -hex-2-enopyranosides in yields of 43-92%. Alkyl 3,4,6-tri- O -acetyl-2-deoxy-αβ- d - lyxo -hexopyranosides are formed as side-products in yields of 2-14 %. Stannic chloride-catalysis is also useful in allylic rearrangement of 3,4,6-tri- O -acetyl-1,5-anhydro-2-deoxy- d - arabino - hex-l-enitol (3,4,6-tri- O -acetyl- d -glucal) which, with methanol or ethanol, affords the corresponding alkyl 4,6-di- O -acetyl-2,3-dideoxy-α- d - erythro -hex-2-enopyranosides in yields of 83 and 94%.

The Synthesis of Sugars from Non-Carbohydrate Substrates

Publisher Summary This chapter describes the syntheses of sugar-type compounds containing four or more carbon atoms, an aldehyde or a ketone group, and a minimum of two hydroxyl groups (or their equivalents, such as amino or thiol groups) with at least one of them being bound to a center of chirality. Among the variety of noncarbohydrate precursors, acetylenes and alkenes have found wide application as substrates for the synthesis of monosaccharides. The parent compounds of all pyranoses—the 2H - and 4H -pyrans—and their derivatives are impractical as substrates for the synthesis of sugars. The formation of furan derivatives in acid-catalyzed dehydrations of carbohydrate substrates is a well known reaction. 1,2-Ethenediyl carbonate (1,3-dioxol-2-one; vinylene carbonate) is a readily available, versatile synthon having pronounced dienophilic properties. For the synthesis of optically active sugars, a number of natural compounds have been successfully employed. The syntheses of sugars described in this chapter demonstrate the general utility of starting materials employed as the precursors of various sugars of desired structure.

Esterification of allylic alcohols with benzoic acid in the presence of diethyl azodicarboxylate and triphenylphosphine

Abstract Stereoselectivity of esterification reaction of some allylic alcohols, mainly unsaturated pyranosides, with benzoic acid in the presence of diethyl azodicarboxylate and triphenyl phosphine was investigated. The reaction was found to proceed with inversion, without allylic rearrangement.

An Improved Synthesis and NMR Spectra of Benzylated Glycals

Abstract Benzylated glycals, unlike their acylated congeners which easily undergo allylic rearrangement, are frequently employed as reactive enol ether type substrates in a variety of electrophilic addition reactions.1–4 Although these compounds are considered to be readily available substrates, reported procedures for their syntheses involve some steps of limited efficiency, chromatographic separations or costly reagents,5–7 and experimental requirements not amenable for large scale preparations. In view of the recent applications of benzylated glycals to syntheses of O-glycosides,1,2 C-glycosyl compounds,3 and β-lactams,4 we have undertaken a study aimed at efficient one step benzylation procedures applicable to pyranoid 1-enitols as well as to their acylated derivatives. This goal was eventually achieved by employing a catalytic phase transfer alkylation system with

Stereoselective synthesis of methyl β-dl-novioside

Abstract Stereoselective synthesis of an antibiotic sugar, methyl β- dl -novioside from 2-(2-furyl)propan-2-ol is described. The key step involved transformation of 2,5-dimethoxy-2,5-dihydrofuran derivative into 2,3-unsaturated pyranos-4-ulose. Its glycosidation followed by reduction, methylation and hydroxylation afforded β- dl -novioside. It has been demonstrated that anomeric configuration of methyl noviosides and novobiocin are opposite to that reported in the literature.

Synthetic conjugates of genistein affecting proliferation and mitosis of cancer cells

This paper describes the synthesis and antiproliferative activity of conjugates of genistein (1) and unsaturated pyranosides. Constructs linking genistein with a sugar moiety through an alkyl chain were obtained in a two-step synthesis: in a first step genistein was converted into an intermediate bearing an ω-hydroxyalkyl substituent, containing two, three or five carbon atoms, at position 7, while the second step involved Ferrier glycosylation reaction, employing glycals. Antiproliferative activity of several genistein derivatives was tested in cancer cell lines in vitro. The most potent derivative, Ram-3 inhibited the cell cycle, interacted with mitotic spindles and caused apoptotic cell death. Neither genistein nor the sugar alone were able to influence the mitotic spindle organization. Our results indicate, that conjugation of genistein with certain sugars may render the interaction of derivatives with new molecular targets.

Novel small molecular inhibitors disrupt the JAK/STAT3 and FAK signaling pathways and exhibit a potent antitumor activity in glioma cells

JAK (Janus kinase)/STAT (signal transducers and activators of transcription) signaling is involved in the regulation of cell growth, differentiation and apoptosis. Constitutive activation of STATs, in particular STAT3, is observed in a large number of human tumors, including gliomas and may contribute to oncogenesis by stimulating cell proliferation and preventing apoptosis, thus it emerges as a promising target for anti-cancer therapy. To investigate the therapeutic potential of blocking STAT3 in glioma cells a set of small synthetic molecules - caffeic acid derivatives, structurally related to AG490 was screened for its ability to inhibit STAT3. Inhibitor 2 (E)-2-cyano-N-[(S)-1-phenylethyl]-3-(pyridin-2-yl)acrylamide was the most effective in inhibition of JAK/STAT3 signaling and at doses ≥ 25 μM significantly reduced the level of phosphorylated JAK1, JAK2 and STAT3 (at Tyr705) and downregulated the expression of known STAT3 targets. In treated cells we observed rapid detachment and rounding of cells associated with reduction of focal adhesion kinase phosphorylation and activity, followed by upregulation of phosphorylated p38, JNK and ERK1/2 levels. Accumulation of cells with fragmented DNA, increases of the cleaved caspase 3 and fragmented PARP levels were detected 24 h after the treatment suggesting ongoing apoptotic cell death. Three human malignant glioblastoma cell lines defective in tumor suppressors TP53 and/or PTEN were susceptible to inhibitor 2 that induced the programmed cell death. Global gene expression profiling revealed modulation of numerous genes in cells treated with inhibitor 2 revealing novel, potential JAK/STAT targets. Our study demonstrates that suitably modified caffeic acid molecules exhibit significant cytotoxic potential toward glioma cells.

The synthesis of mixed carbonates from alcohols, dialkyl azodicarboxylate and tris(dimethylamino)-phosphine

Abstract A mild method for the synthesis of mixed carbonates from alcohols, dialkyl azodicarboxylate and tris(dimethylamino)-phosphine is described. The yields of carbonates are in the range 22–88%.

In vitro antiviral activity of some uridine derivatives of 2-deoxy sugars against classical swine fever virus

Classical swine fever virus glycoproteins: E2, E(rns) (E0) and E1 are detected on the external part of viral particles and play a major role in the initial stages of viral infection. They form heterodimeric and homodimeric complexes needed to effectively infect host cells. Some glycosylation inhibitors, such as tunicamycin, which act at the early stages of glycan chain processing, can influence, not only glycosylation, but also the stability of E2 and E(rns) glycoproteins, effectively inhibiting the formation of glycoprotein complexes and virus yield. In our study we tested two of newly designed uridine derivatives of 2-deoxy sugars, IW3 and IW7 mimicking part of tunicamycin. We showed that inhibitors effectively arrest viral growth with IC(50) of 9 and 7microg/ml respectively, without significant toxicity for mammalian cells. Moreover, IW3 and IW7 reduced the formation of viral glycoproteins E2 and E(rns) in a dose-dependent manner. These compounds were further studied in order to elucidate the molecular mechanism of the antiviral effect using mammalian SK6 and insect Sf9 cell lines. We found that they inhibit N-glycosylation process of viral proteins at the late stage of glycan modification characteristic for mammalian cells. Due to the observed antiviral effect accompanied by low cytotoxicity, these inhibitors are potential candidates for anti-pestivirus therapy.

Unsaturated genistein disaccharide glycoside as a novel agent affecting microtubules.

Genistein, due to its recognized chemopreventive and antitumor potential, is a molecule of interest as a lead compound in drug design. While multiple molecular targets for genistein have been identified, so far neither for this isoflavonoid nor for its natural or synthetic derivatives disruption of microtubules and mitotic spindles has been reported. Here we describe such properties of the synthetic glycosidic derivative of genistein significantly more cytotoxic than genistein, 7-O-(2,3,4,6-tetra-O-acetyl-beta-D-galactopyranosyl)-(1-->4)-(6-O-acetyl-hex-2-ene-alpha-D-erythro-pyranosyl)genistein, shortly named G21. We found that G21 causes significant mitotic delay, frequent appearance of multipolar spindles, and alteration of the interphase microtubule array.