Histone deacetylase is a metallo-enzyme with zinc at the active site. Compounds having a zinc-binding moiety, such as, for example, a hydroxamic acid group or a carboxylic acid group, can inhibit histone deacetylase. Histone deacetylase can repress gene expression, including expression of genes related to tumor suppression. Accordingly, inhibition of histone deacetylase can provide an alternate route for treating cancer, hematological disorders, e.g., hemoglobinopathies, and genetic related metabolic disorders, e.g., cystic fibrosis and adrenoleukodystrophy.

Histone deacetylase inhibitors

Publisher Summary The C-nucleosides are a group of C-glycosylated heterocycles in which the anomeric carbon atom is attached to the heterocycle by a C-C bond. C-nucleosides have been mainly from fermentation sources, and have been found to exhibit a variety of interesting biological properties. Pyrazomycin has significant antiviral activity. Formycin, formycin B, and oxazinomycins exhibit, in addition, antitumor activity. The biological importance of most of the naturally occurring C-nucleosides has prompted the exploration of synthetic routes leading to these compounds and their analogs. As synthetic targets, the C-nucleosides have deceptively simple structures, and the design of synthetic routes to them must take two important factors into account. Firstly, the methods selected for C-C bond formation at the anomeric center should be stereocontrolled because the structures known thus far are, with two exceptions, β-D-glycosyl compounds. Secondly, the carbon atom attached to the glycosyl group in a C-nucleoside precursor should be appropriately substituted or be amenable to substitution, so as to allow the elaboration of the other heterocyclic portion of the molecule.

Synthesis of naturally occurring C-nucleosides, their analogs, and functionalized C-glycosyl precursors.

Publisher Summary The chapter focuses on the methods for determination of conformation of sugars and their derivatives The study of the conformations of organic molecules pointed out that six membered ring-systems can exist free from bond-angle strain, in two puckered forms, the flexible or asymmetric form, and the rigid or symmetric (chair) form Boat or skew conformations are considered possible if the nonbonded interactions between the substituents in the chair conformation are too large The conformational analysis of saturated five and six-membered heterocycles, presenting data relevant to the carbohydrate field, is also presented The various techniques discussed in the chapter are X-ray crystallography andspectroscopic methods—namely infrared spectroscopy, microwave spectroscopy, and nuclear magnetic resonance spectroscopy Methods based on optical activity and those that involve formation of complexes in cuprammonia, and dipole moments are also discussed Several theoretical studies on the conformations of the aldopyranoses are also reported By calculating the extent of atomic (Van der Waals) overlap of non-bonded atoms, the relative stabilities of the chair conformations of the aldopyranoses are estimated The chapter also describes methods for conformations of acyclic sugars and their derivatives, pyranoid sugar derivatives, and furanoid sugar derivatives, in their crystalline state and in solution The chapter also discusses anomeric effect and empirical approaches to predict favorable conformation

Conformational Analysis of Sugars and Their Derivatives

The present invention provides highly active cyclic-di-nucleotide (CDN) immune stimulators that activate DCs via a recently discovered cytoplasmic receptor known as STING (Stimulator of Interferon Genes). In particular, the CDNs of the present invention are provided in the form of a composition comprising one or more cyclic purine dinucleotides induce STING-dependent type I interferon production, wherein the cyclic purine dinuclotides present in the composition are substantially pure 2', 5', 2', 5' and 2', 5 ',3 ',5' CDNs, and prefereably Rp,Rp stereosiomers thereof.

Compositions and methods for activating "stimulator of interferon gene"-dependent signalling

Conformations of the alditols

Structure of osotriazoles of the sugars. Conformational and configurational correlations of the polyhydroxyalkyl chain

Synthesis of 2,6-dideoxy-α-L-lyxo- and 2,6-dideoxy-α-L-arabino-hexopyranosyl halides

Reactions of the 3-oxime 2-phenylhydrazone and mixed bishydrazones of dehydro-L-ascorbic acid: Conversion into substituted triazoles and pyrazolinediones

Mono- and bis-hydrazone of D-erythrose and 2,3-Dioxo-y-butyrolactone

Hypoxanthine, guanine, and 6-thiopurine nucleosides of 6-deoxy-D-allofuranose have been prepared as potential antitumor agents. Thus, reaction of 6-deoxy-beta-D-allofuranosyl bromide (1) with the trimethylsilyl derivatives of hypoxanthine and guanine afforded mixtures of the 9- and the 7-substituted bases, which were separated and deblocked with ammonia to give 9-(6'-deoxy-beta-D-allofuranosyl)hypoxanthine (6), 7-(6'-deoxy-beta-D-allofuranosyl)hypoxanthine (7), 9-(6'-deoxy-beta-D-allofuranosyl)guanine (8), and 7-(6'-deoxy-beta-D-allofuranosyl)guanine (9). The two nucleosides with the purine joined at the N-9 position, namely, 6 and 8, are easily distinguished from the other two nucleosides (7 and 9), having N-7 junctions, by their NMR spectra. Reaction of 1 with the trimethylsilyl derivative of 6-chloropurine afforded 10, which upon treatment with thiourea and deblocking gave 9-(6'-deoxy-beta-D-allofuranosyl)-6-thiopurine (12). The hypoxanthine and guanine nucleosides showed no inhibition of mouse leukemia L1210 when tested in vivo, but the thiopurine nucleoside 12 showed strong inhibition of growth of L1210 both in vivo and in vitro. Compound 7 strongly inhibited purine nucleoside phosphorylase (KI = 8.8 X 10(-5) M), while compounds 8, 9, 6, and 12 were inactive.

Hassan S. El Khadem

Papers

Structure of osotriazoles of the sugars. Conformational and configurational correlations of the polyhydroxyalkyl chain

Synthesis of 2,6-dideoxy-α-L-lyxo- and 2,6-dideoxy-α-L-arabino-hexopyranosyl halides

Reactions of the 3-oxime 2-phenylhydrazone and mixed bishydrazones of dehydro-L-ascorbic acid: Conversion into substituted triazoles and pyrazolinediones

Mono- and bis-hydrazone of D-erythrose and 2,3-Dioxo-y-butyrolactone

Synthesis of Hypoxanthine, Guanine, and 6-Thiopurine Nucleosides of 6-Deoxy-D-allofuranose