50 Years of Image Analysis

Advances in the chemistry of tetrahydroquinolines.

Claisen rearrangement over the past nine decades.

The natural killer T (NKT) cell ligand α-galactosylceramide (α-GalCer) exhibits profound antitumor activities in vivo that resemble interleukin (IL)-12–mediated antitumor activities. Because of these similarities between the activities of α-GalCer and IL-12, we investigated the involvement of IL-12 in the activation of NKT cells by α-GalCer. We first established, using purified subsets of various lymphocyte populations, that α-GalCer selectively activates NKT cells for production of interferon (IFN)-γ. Production of IFN-γ by NKT cells in response to α-GalCer required IL-12 produced by dendritic cells (DCs) and direct contact between NKT cells and DCs through CD40/CD40 ligand interactions. Moreover, α-GalCer strongly induced the expression of IL-12 receptor on NKT cells from wild-type but not CD1−/− or Vα14−/− mice. This effect of α-GalCer required the production of IFN-γ by NKT cells and production of IL-12 by DCs. Finally, we showed that treatment of mice with suboptimal doses of α-GalCer together with suboptimal doses of IL-12 resulted in strongly enhanced natural killing activity and IFN-γ production. Collectively, these findings indicate an important role for DC-produced IL-12 in the activation of NKT cells by α-GalCer and suggest that NKT cells may be able to condition DCs for subsequent immune responses. Our results also suggest a novel approach for immunotherapy of cancer.

The natural killer T (NKT) cell ligand _-galactosylceramide′ demonstrates its immunopotentiating effect by inducing′ intreleukin (IL)-12 production by dendritic cells and IL-12′ receptor expression on NKT cells.

Over the past decade, large strides have been achieved in the invention of methods for the direct enantioselective addition of alkynes and metal alkynylide nucleophiles into prochiral aldehydes, ketones, and imines. This review highlights and compares the available methods for these transformations.

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The Enantioselective Addition of Alkyne Nucleophiles to Carbonyl Groups

Associated with the CD1d protein, KRN 7000, a potent synthetic α-galactosylceramide, is known to activate the invariant NKT immune cells. This stimulation then leads to the production of different cytokines modulating a T(H)1/T(H)2 immune response balance involved in protection against several pathologies such as autoimmune diseases and cancers. Various efforts have been made toward the synthesis of simple and more functionalized analogues in order to selectively induce T(H)1 or T(H)2-type cytokine production. Since the discovery of KRN 7000, structure-activity relationships, crystallographic and modelling studies have pointed to the potential of several GalCer analogues in term of selective bioactivity, and have highlighted interesting elements in order to better understand the recognition and activation mechanisms of immune iNKT cells. By presenting an up-to-date library of analogues, collecting recent breakthroughs done in crystallography and molecular modelling, and relating them to the available biological results, we hope that this review will highlight and help the scientific community in their KRN research.

The stimulating adventure of KRN 7000

Alkynylation of chiral aldehydes: alkoxy-, amino-, and thio-substituted aldehydes.

1,3-Dibromo-5,5-dimethylhydantoin, a useful reagent for aromatic bromination

Preferred Conformations of C-Glycosides. 14. Synthesis and Conformational Analysis of Carbon Analogs of the Blood Group Determinant H-Type II

After a brief account of the syntheses previously described in literature, several approaches of the antiangiogenic sesquiterpene fumagillin are described. Particularly, a Claisen-Ireland ring-closing metathesis strategy allowed the stereoselective preparation of several advanced intermediates in the fumagillin synthesis. Fumagillin 1, isolated in 1951 by Elbe and Hanson (1) from the microbial organism Aspergillus fumi- gatus, is representative of a class of sesquiterpenes such as ovalicin 2 (2) and FR 65814 3 (3), which display interesting biological activities. Fumagillin itself was first described as an antimicrobial agent, but more recently, Folkman and coworkers (4) discovered that this compound is a potent and selective inhibitor of angiogenesis. The same activity has been reported later for ovalicin 2 (5) which, as FR 65814 3, is also a potent immunosuppressor (3). More recently, semisynthetic compound TNP-470 4 (6,7) showed a better therapeutic index than fumagillin 1. The recent discovery that methionine aminopeptidase II (MetAp-II) is selectively inhibited by fumagillin 1 (8) and the X-ray structure of the covalent complex between fumagillin 1 and MetAp-II (9) increases the interest of the synthesis of fumagillin 1 and of new fumagillin analogs (10,11). After the pioneering synthesis of racemic fumagillin 1 by Corey in 1972 (12), this area of research remained dormant for 25 years. But in the past 5 years, 3 syntheses of (-)-fumagillin 1 or (-)-fumag- illol 5, the direct precursor of fumagillin 1, (13-15) as well as two syntheses of racemic fumagillin 1/fumagillol 5 (16,17) have been published. From a biogenetic point of view, it has been demonstrated that fumagillin 1 and ovalicin 2 have as a common precursor cis-farnesyl pyrophosphate (18,19). This biogenetic pathway has been recently reinforced by the discovery of a new metabolite 6 in the fermentation broth producing fumagillin 1 (20). The structure of fumagillin 1 is characterized by the presence of six stereogenic centers, of a func- tionalized cis diol and of two epoxides. The spiro epoxide is easily the subject of nucleophilic attack and is essential (21) for the anti angiogenesis activity. Thus, the nucleophilic attack of histidine 231 of MetAp II gave rise to the formation of a covalent bond shown in the X-ray structure of the complex between 1 and MetAp II (9). From a synthetic point of view, a possible precursor of fumagillin could be the terpene-like derivative 7 characterized by the presence of four double bonds. The selective func- tionalization of three of these double bonds can be considered as the main challenge in the synthesis of 1. Owing to the relative reactivity of these double bonds, the sequence of functionalization of each alkene is also fundamental.

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Arnaud Haudrechy

Papers

The stimulating adventure of KRN 7000

Alkynylation of chiral aldehydes: alkoxy-, amino-, and thio-substituted aldehydes.

1,3-Dibromo-5,5-dimethylhydantoin, a useful reagent for aromatic bromination

Preferred Conformations of C-Glycosides. 14. Synthesis and Conformational Analysis of Carbon Analogs of the Blood Group Determinant H-Type II

Progress in fumagillin synthesis