Of sinefungin

Chrebet, G. L., Wisniewski, D., Perkins, A. L., Deng, Q., Kurtz, M. B., Marcy, A., and Parent, S. A. (2005). Cell-based assays to detect inhibitors of fungal mRNA capping enzymes and characterization of Sinefungin as a cap methyltransferase inhibitor.J. Biomol. Screen. 10, 355-364. 

This alkylation strategy has been successfully implemented to the diastereoselective synthesis of a number of biologically active compounds,17 19 32 72 73 including the orally active HIV protease inhibitor Crixivan (>95% de)17-19 and nucleoside antibiotic (+)-sinefungin (51) (>99% de).72 The C-6 amine stereochemistry of (+)-sinefungin was set by a highly diastereoselective allylation of (lS,2/ )-l-amino-2-indanol-derived oxazolidinone 52 (Scheme 24.10). 

A synthesis of sinefungin has been described, using a nitro-aldol condensation between a dialdose derived from adenosine and an -nitro-aminoacid derivative to build the required Cj Q-carbon skeleton... 

A synthesis of sinefungin (22) proceeded from a condensation of N -benzoyl-2, 3 -0-isopropylidene-adenosine 5 -aldehyde with nitromethane, the nitroaldol then being reduced to the corresponding 5, 6 -dideoxy-6 -nitro derivative, which was further condensed with an L-aspartic acid derivative leading to (22) and its 75... 

A synthesis of sinefungin (29) and its 6 -epimer has been reported, which uses the adenosine-based thiopyridinyl ester (30). This underwent photchemical reaction with the alkene (31) to form the skeleton required for the products (Scheme 6). 

A series of sinefungin analogues have been prepared by chain extension reactions on a known 5-cyano-phosphonate derivative of ribose. A biosynthetic study on sinefungin using doubly-labelled substrates has shown that adenosine is a precursor, the ribose residue being incorporated intact. 

A study of the biosynthesis of sinefungin using a cell-free extract of incarnatus suggests the immediate precursor to be L-arginine, and a biosynthetic scheme is proposed. 

Amur SG, Shanker G, Cochran JM, Ved HS, Pieringer RA (1986) Correlation between inhibition of myelin basic protein (arginine) methyltransferase by sinefungin and lack of compact myelin formation in cultures of cerebral cells from embryonic mice. J Neurosci Res 16 367-376 An W, Kim J, Roeder RG (2004) Ordered cooperative functions of PRMTl, p300, and CARMl in transcriptional activation by p53. Celll 17 735-748... 

Scheme 4 inactivation of ACS through reaction of its cofactor PLP with the inhibitors (a) PLP forms a ketimine with aminoethoxyvinyigiycine (AVG) (b) PLP forms oxime with AMA, the aminooxy anaiogue of SAM (c) ACS inactivated by antifungai antibiotic sinefungin, the anaiogue of SAM. in this case, the structure of inhibitory adduct is stiii unknown ( ). PLP is marked in biue. Notations are as in Schemes 2 and 3. 

ACS isozymes differ from each other in their sensitivity to inhibitors. For example, the eight catalytically active ACS isozymes from Arabidopsis have Ki values for AVG and sinefungin ranging from 0.019 to 0.8 and 0.15 to 12pmol, whereas those from the crude extract preparation of tomato fruit have 1) values for the same inhibitors ranging from 0.2 to 10 and 1.0 to 25 pmol, respectively. ... 

Vedel, M., Lawrence, F., Robert-Gero, M. and Lederer, E. (1978) The antifungal antibiotic sinefungin as a very active inhibitor of mefhyltransferases and of the transformation of chick embryo fibroblasts by Rous sarcoma virus. Biochemical and Biophysical Research Communications, 85, 371-376. 

G Schluckebier, M Kozak, N Bleimling, E Weinhold, W Saenger. Differential binding of S-adenosylmethionine, S-adenosylhomocysteine and sinefungin to the adenine-specific DNA methyltransferase M.Taql. J Mol Biol 265 56-67, 1997. 

The aldol reaction illustrated in eq 2 has been applied to the targeted synthesis of a number of complex molecules including Tylosin, Hapalosin, the antibiotic Sinefungin, and the HIV protease Saquinavir inhibitor. Oxazolidinone-type chiral auxiliaries derived from 1 have also been employed for the control of Diels-Alder reactions of attached acryloyl or crotonyl groups. ... 

A swap of the methyl carbon with nitrogen in aza-AdoMet leads to sinefungin (see Fig. 2g)—a natural nucleoside antibiotic found in Streptomyces griseolus. Such reverse chemistry additionally enhances the chemical stability of cofactor. Because of the positive charge of the protonated amine and correct chirahty at the carbon center, sinefungin has an extremely high inhibitory potential for AdoMet-dependent methyltransferases. 

On feeding stereospecifically tritiated samples of ornithine to Streptomyces griseolus, it was found that the 5-pro-S hydrogen was lost on incorporation into sinefungin 274 so that bond formation was accompanied by inversion of configuration (282). 

Sinefungin is an adenine derivative, isolated from Streptomyces griseolus and it effectively inhibits VV mRNA (guanine-7-)methyltransferase and hence inhibits methylation of its mRNA [18]. 

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