While natural and synthetic N-nucleosides are vulnerable to enzymatic and acid-catalyzed hydrolysis of the nucleosidic bond, their C-analogues are much more stable. Several C-nucleosides are naturally occurring compounds, e.g., pseudouridine (isolated from the yeast t-RNA) and showdomycin (an antibiotic). Development of novel synthetic methodologies allowed the preparation of a large variety of synthetic analogues, which found numerous applications in medicinal chemistry and chemical biology. Most important biologically active C-nucleosides are the inhibitors of purine nucleosides phosphorylase or IMP dehydrogenase. A number of artificial aryl-C-nucleosides capable of π-stacking are being vigorously investigated as building blocks in chemical biology. In the past few years, several Artificial Expanded Genetic Information Systems (AEGIS)1 have been successfully developed as prime examples of synthetic biology, a newly emerging interdisciplinary area, with the ultimate goal to design systems where high-level behaviors of the living matter are mimicked by artificial chemical systems.2,3

C-nucleosides: synthetic strategies and biological applications.

Twenty-two lycorine-related compounds were investigated for in vitro antitumor activity using four cancer cell lines displaying different levels of resistance to proapoptotic stimuli and two cancer cell lines sensitive to proapoptotic stimuli. Lycorine and six of its congeners exhibited potency in the single-digit micromolar range, while no compound appeared more active than lycorine. Lycorine also displayed the highest potential (in vitro) therapeutic ratio, being at least 15 times more active against cancer than normal cells. Our studies also showed that lycorine exerts its in vitro antitumor activity through cytostatic rather than cytotoxic effects. Furthermore, lycorine provided significant therapeutic benefit in mice bearing brain grafts of the B16F10 melanoma model at nontoxic doses. Thus, the results of the current study make lycorine an excellent lead for the generation of compounds able to combat cancers, which are naturally resistant to proapoptotic stimuli, such as glioblastoma, melanoma, non-small-cell-lung cancers, and metastatic cancers, among others.

Lycorine, the Main Phenanthridine Amaryllidaceae Alkaloid, Exhibits Significant Antitumor Activity in Cancer Cells That Display Resistance to Proapoptotic Stimuli: An Investigation of Structure−Activity Relationship and Mechanistic Insight

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 This chapter discusses the chemical and biological aspects of Narcissus alkaloids. Numerous alkaloids have been isolated from Narcissus speciesasaresult of the continuing search for novel alkaloids with pharmacological activity in the Amaryllidaceae family. The alkaloids isolated from this genus, classified in relation to the different skeleton types. The different Narcissus wild species and intersectional hybrids, grouped into subgenera and sections, with their corresponding alkaloids, arranged according to their ring system are listed. The biosynthetic pathways of Narcissus alkaloids includes: (1) enzymatic preparation of the precursors, (2) primary cyclization mechanisms, (3) enzymatic preparation of intermediates, (4) secondary cyclization, diversification, and restructuring. The chapter discusses proton nuclear magnetic resonance ( 1 H NMR), carbon nuclear magnetic resonance ( 13 C NMR), and mass spectrometry (MS) for Narcissus alkaloids. A list of the different Narcissus alkaloids, their spectroscopic properties, and literature with the most recent spectroscopic data is given. Several Narcissus extracts shows the following activities: antiviral, prophage induction, antibacterial, antifungal, antimalarial, insecticidal, cytotoxic, antitumor, antimitotic, antiplatelet, hypotensive, emetic, acetylcholine esterase inhibitory, antifertility, antinociceptive, chronotropic, pheromone, plant growth inhibitor, and allelopathic.

Chapter 3 Chemical and Biological Aspects of Narcissus Alkaloids

A new crystalline antibiotic, minimycin1), C9H11NO7, was isolated from the culture broth of Streptomyces hygroscopicus. Isolation and properties of the new antibiotic are described. Minimycin is active against both Gram-positive and Gram-negative bacteria, and also possesses significant antitumor activity against transplantable tumors.

Yuzo Nakagawa

Papers

Structure of a new class of C-nucleoside antibiotic, showdomycin.

Mass spectrometry of some amaryllidaceae alkaloids.

757. Stereochemistry of reduction products of 1-acetyl-lycorin-2-one