Rahman Studies in Natural Products Chemistry

1. Auflage 2014
ISBN: 978-0-444-63282-1
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: 6 - ePub Watermark

E-Book, Englisch, Band Volume 42, 500 Seiten

Reihe: Studies in Natural Products Chemistry

Natural products in the plant and animal kingdom offer a huge diversity of chemical structures that are the result of biosynthetic processes that have been modulated over the millennia through genetic effects. With the rapid developments in spectroscopic techniques and accompanying advances in high-throughput screening techniques, it has become possible to isolate and then determine the structures and biological activity of natural products rapidly, thus opening up exciting new opportunities in the field of new drug development to the pharmaceutical industry.The series also covers the synthesis or testing and recording of the medicinal properties of natural products, providing cutting edge accounts of the fascinating developments in the isolation, structure elucidation, synthesis, biosynthesis and pharmacology of a diverse array of natural products. - Describes the chemistry of bioactive natural products - Contains contributions by leading authorities in the field - Presents exciting sources of new pharmacophores

Autoren/Hrsg.

Rahman, Atta-ur-

Leseproben

Chapter 1 Glycosphingolipid Ligands for Invariant Natural Killer T cells as Immunostimulants
Takuya Tashiro; Kenji Mori    Glycosphingolipid Synthesis Group, Laboratory for Immune Regulation, Research Center for Allergy and Immunology (RCAI), RIKEN, Wako-shi, Saitama, Japan Abstract
Noncytotoxic anticancer a-galactosphingolipid agelasphin-9b (1) was isolated in 1993 from an Okinawan marine sponge. Since then, a large number of natural and synthetic glycolipids were bioassayed as immunostimulants, which activate natural killer T cells to generate cytokines such as interferon ? (IFN-?) and interleukin 4 (IL-4). Some of them (2–6) are known to be drug candidates for autoimmune disease or cancer. Our chapter will review the methods used for the synthesis of these compounds, and also the structure–activity relationships among them. Recent biological and X-ray crystallographic studies show that each of the glycolipids is a ligand to make a complex with CD1d protein, and the complex can be recognized by T-cell receptor to induce the generation of cytokines such as IFN-? and IL-4. Accordingly, it is important to identify the naturally occurring ligand(s) in animal bodies. In 2011, 7 (ß-GluCer) was proposed as the natural and endogenous ligand. Synthesis and bioassay of 7 and its relatives will also be reviewed. Finally, future clinical application of these noncytotoxic immunostimulants will be discussed. (for a previous review please, see K. Mori, T. Tashiro, Heterocycles, 2011, 83, 951–1003.) Keywords Cytokines Glycolipids KRN7000 Natural killer T cell T-cell receptor Abbreviations APC antigen-presenting cell CD cluster of differentiation Cer ceramide EAE experimental autoimmune encephalomyelitis Gal galactose; galactosyl Glc glucose; glucosyl IFN interferon iGb isogloboside IL interleukin Lac lactose; lactosyl MD molecular dynamics NK natural killer SAR structure–activity relationship SPR surface plasmon resonance TCR T-cell receptor Th helper T Introduction
The first glycosphingolipids reported in 1993 as immunostimulants were agelasphins such as agelasphin-9b (1, Fig. 1) [1]. Natori and Koezuka (Kirin Brewery Co.) in cooperation with Higa (University of the Ryukyus) isolated agelasphins from an extract of the Okinawan sponge Agelas mauritianus Carter (1883). As depicted in 1, agelasphin-9b was the first example of a cerebroside having an a-galactosyl linkage. It showed no cytotoxicity at all in vitro, but exhibited strong anticancer activity in vivo in mice and humans due to its immunostimulative activity. Figure 1 Structures of agelasphin-9b (1) and KRN7000 (2). Based on the anticancer activity of 1, Morita et al. [2] synthesized a large number of analogs of 1 to clarify the structure–activity relationships (SAR). KRN7000 (2), an anticancer drug candidate, was disclosed in 1995 as the outcome of their extensive efforts. In 1997, Taniguchi and his coworkers showed that KRN7000 (2) was a ligand which complexed with CD1d (CD = cluster of differentiation) protein, a glycolipid-presenting protein on the surface of the antigen-presenting cells (APCs) of the immune system [3,4]. The two lengthy alkyl chains of 2 are bound in grooves in the interior of the CD1d protein, and the galactose head group of 2 is presented to the antigen receptors of the natural killer (NK) T cells of the immune system (Fig. 2). Figure 2 Natural killer T (NKT) cells provide an innate-type immune response upon recognition of T-cell receptor with CD1d-presented antigens such as KRN7000. After activation upon recognition of the CD1d/2 complex, NKT cells release both helper T (Th) 1 and Th2 types of cytokines in large quantities. Th1-type cytokines such as interferon (IFN)-? mediate protective immune functions such as tumor rejection, whereas Th2-type cytokines such as interleukin (IL)-4 mediate regulatory immune functions to ameliorate autoimmune diseases. Th1 and Th2 cytokines can antagonize each other's biological actions. Because of this antagonism, use of KRN7000 for clinical therapy has not been successful yet. Accordingly, a number of research groups in the world began synthesis of glycosphingolipids, which induce NKT cells to produce preferentially either Th1- or Th2-type cytokines. This review summarizes the results of their efforts, including ours, to design more potent and selective immunostimulants so as to produce either Th1 or Th2 cytokines. Identification of an endogenous ligand in mice and humans is still a remaining problem, which will also be reviewed. Chemistry and SAR of KRN7000 and related compounds were reviewed many times by both chemists and immunologists [5–13]. Synthesis of KRN7000
Due to fascinating bioactivities, KRN7000 (2) has continuously attracted organic chemists’ synthetic interest. After the disclosure of the structure 2 by Kirin Brewery [2], many reports on the synthesis of 2 were published [5,7,9]. KRN7000 (2) is an a-galactosylated ceramide (Cer) and consists of three parts as follows: D-galactose, C18-D-ribo-phytosphingosine, and hexacosanoic acid (cerotic acid). Two key steps in the synthesis of 2 are preparation of D-ribo-phytosphingosine with the proper stereochemistry and a-selective galactosylation. D-ribo-C18-Phytosphingosine, (2S,3S,4R)-2-aminooctadecane-1,3,4-triol, is one of the major natural sphingoid bases, and its ceramides and glycosyl ceramides are widely spread in nature. Therefore, its synthesis in chemically and optically pure form has been a fascinating subject [14]. Preparation of the Sphingosine Part
To construct the phytosphingosine moiety, Ogawa's procedure was adopted [15] in the early phase of the synthesis of 1, 2 and their analogs [1,2]. The procedure uses D-galactose to construct the three contiguous stereocenters of D-ribo-phytosphingosine by using the asymmetry at C-3, -4, and -5 of D-galactose [15]. Subsequently, an alternative procedure employing D-lyxose was reported in a practical synthesis of 2 [16]. Although both protocols can give chemically and diastereomerically pure D-ribo-phytosphingosine, they are redundant and require cumbersome multistep transformations. Fortunately, D-ribo-C18-phytosphingosine is now manufactured using a mutant strain of the yeast Pichia ciferii, and can be purchased at reasonable price [17]. The commercial availability of D-ribo-phytosphingosine was a very welcome news for those who engaged in sphingosine and ceramide synthesis, and accelerated the SAR studies on 2 (Fig. 3). Figure 3 Retrosynthetic analysis of KRN7000 in the early phase. As we discussed below, the sphingosine part of 2 should have 2S,3S,4R absolute configuration to show the potent immunostimulatory activities. This is the major stereostructure of the natural phyto-type sphingoid bases, and D-ribo-phytosphingosine manufactured by fermentation also has this configuration. On the other hand, the inexpensively available D-ribo-phytosphingosine has the fixed C18-chain length. To construct the library of analogs to investigate SAR study on the sphingosine chain, the previously noted chiral pool-based synthesis employing sugars (e.g., Ogawa's protocol [15]) is one of the practical methods. Synthesis of 2 starting from Garner's aldehyde [18] provides the various divergent synthetic procedures [19]. Z-Selective cross-metathesis reaction followed by dihydroxylation reported by Hoveyda and coworkers [20] is also a powerful method to prepare many kinds of phytosphingosine analogs (Fig. 4). Figure 4 Divergent synthesis of phytosphingosine part. a-Selective Galactosylation
In most cases, the a-anomer of mono-galactosylated ceramides can be easily separated from the ß-one by column chromatography. In addition, galactosylation reaction of a...