Imino sugar

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Iminosugars , outdated also known as aza sugars ( engl. Iminosugar ), are a biologically , pharmacologically and chemically important class of substances that are counted among the alkaloids . There are sugar - analogues , which took one endocyclic oxygen atom , a nitrogen atom carry. In contrast, the amino sugars carry the nitrogen on and not in the ring of the sugar molecule.

Natural occurrence

Iminosugars are secondary metabolites in a number of plants. Mulberry trees ( Morus ) contain a high proportion of various iminosugars. In 1976, 1-deoxynojirimycin (DNJ) was the first iminosugar to be isolated from the roots of mulberry trees and initially referred to as molanolin . DNJ is also found in other components of the mulberry trees, such as the leaves. The white mulberry ( Morus alba ) in particular contains relatively high concentrations . The DNJ content is in the range of about 0.1%. By optimizing the harvest and drying, the content can be increased up to 1.5%.

The calystegins form a subgroup of the iminosugars . These are hydroxylated nortropane alkaloids. These potent glycosidase inhibitors have been isolated in potatoes , peppers, and eggplant . The concentration is up to 100 mg per kg of dry matter . The highest concentration is found in the peel of the fruit. It is assumed that the calystegins in the plant function as an anti-eating agent .

Pharmacological importance

Miglustat, an imino sugar approved for the treatment of two lysosomal storage diseases.
1-Deoxygalactonojirimycin is a pharmacological chaperone . It should help mutated variants of the enzyme α-galactosidase A to develop correctly .

A number of iminosugars are reversible, competitive inhibitors of enzymes whose “natural” substrate is the corresponding “normal” sugar. In contrast to covalently binding inhibitors, which inhibit irreversibly, this type of inhibition can be better controlled. The main pharmacological interest is the antibacterial and antiviral potential of iminosugars. There are also promising approaches for the treatment of malignant tumors , diabetes mellitus and obesity , which are based primarily on the selective inhibition of certain enzymes, for example glucosidases.

Miglustat (= n -butyldeoxynojirimycin, NB-DNJ) is a glucosylceramide synthase inhibitor that is approved for the substrate reduction therapy of two lysosomal storage diseases ( Niemann-Pick disease type C and Gaucher's disease type 1) . 1-Deoxygalactonojirimycin (= DGJ) received an approval recommendation from the Committee for Medicinal Products for Human Use for the treatment of Fabry's disease under the non- proprietary name Migalastat in April 2016 and has been approved in the EU since May 2016.

In traditional Chinese medicine (TCM), the leaves of the white mulberry are used to treat and prevent diabetes mellitus. The roots are used under the name Sang-bai-pi ( Japanese Sohakuhi ) as an anti-inflammatory , diuretic , antitussive and antipyretic . As a glucosidase inhibitor, 1-deoxygalactonojirimycin is able to lower the glucose level in the blood.

Synthesis and history

Nojirimycin, an analogue of D -glucose
In comparison, the structure of α- D -glucose

In 1966, the German natural product chemist Hans Paulsen synthesized 1-deoxynojirimycin, the first iminosugars at the University of Hamburg , before iminosugars were found in nature. Also in 1966, 5-amino-5-deoxy- D- glucose was isolated from the fermentation broth of Streptomyces lavaendulae and named norjirimycin by the discoverers .

The synthesis of the iminosugars is relatively complex and difficult , primarily due to the number of stereocenters .

literature

Individual evidence

  1. ↑ M. Yagi, T. Kouno et al. a .: The structure of maranoline, a piperidine alkaloid from Morus species. In: Nippon Nogei Kagaku Kaishi. 50, 1976, pp. 571-572.
  2. ↑ T. Kimura, K. Nakagawa et al. a .: Simple and rapid determination of 1-deoxynojirimycin in mulberry leaves. In: BioFactors. Volume 22, Numbers 1-4, 2004, pp. 341-345, PMID 15630308 .
  3. ^ W. Song, HJ Wang u. a .: Phytochemical profiles of different mulberry (Morus sp.) species from China. In: Journal of Agricultural and Food Chemistry . Volume 57, Number 19, October 2009, pp. 9133-9140, doi : 10.1021 / jf9022228 . PMID 19761189 .
  4. ↑ B. Islam, SN Khan et al. a .: Novel anti-adherence activity of mulberry leaves: inhibition of Streptococcus mutans biofilm by 1-deoxynojirimycin isolated from Morus alba. In: Journal of Antimicrobial Chemotherapy . Volume 62, Number 4, October 2008, pp. 751-757, doi : 10.1093 / jac / dkn253 . PMID 18565974 .
  5. ↑ a b T. Kimura, K. Nakagawa and a .: Food-grade mulberry powder enriched with 1-deoxynojirimycin suppresses the elevation of postprandial blood glucose in humans. In: Journal of agricultural and food chemistry. Volume 55, Number 14, July 2007, pp. 5869-5874, doi : 10.1021 / jf062680g . PMID 17555327 .
  6. ↑ N. Asano, A. Kato et al. a .: The effects of calystegines isolated from edible fruits and vegetables on mammalian liver glycosidases. In: Glycobiology. Volume 7, Number 8, December 1997, pp. 1085-1088, PMID 9455909 .
  7. ↑ F. Schieweck: Stereoselective synthesis of iminosugars. University of Wuppertal, Department of Chemistry, 2000, p. 5.
  8. ^ SV Evans, LE Fellows u. a .: Glycosidase inhibition by plant alkaloids which are structural analogues of monosaccharides. In: Phytochemistry. Volume 24, Number 9, 1985, pp. 1953-1955. doi : 10.1016 / S0031-9422 (00) 83099-X
  9. ↑ RA Gruters, JJ Neefjes u. a .: Interference with HIV-induced syncytium formation and viral infectivity by inhibitors of trimming glucosidase. In: Nature . Volume 330, Number 6143, 1987 Nov 5-11, pp. 74-77, doi : 10.1038 / 330074a0 . PMID 2959866 .
  10. ↑ MJ Humphries, K. Matsumoto et al. a .: Inhibition of experimental metastasis by castanospermine in mice: blockage of two distinct stages of tumor colonization by oligosaccharide processing inhibitors. In: Cancer research . Volume 46, Number 10, October 1986, pp. 5215-5222, PMID 3093061 .
  11. ↑ E. Truscheit, W. Frommer u. a .: Chemistry and Biochemistry of Microbial α-Glucosidase Inhibitors. In: Angewandte Chemie International Edition. Volume 20, Number 9, 1981, pp. 744-761. doi : 10.1002 / anie.198107441
  12. ↑ W. Puls, U. Keup et al: Glucosidase inhibition: a new approach to the treatment of diabetes, obesity, and hyperlipoproteinaemia. In: Natural Sciences . Volume 64, 1977, pp. 536-537.
  13. ↑ Galafold . European Medicines Agency . April 1, 2016.
  14. ↑ N. Asano: Naturally occuring iminosugars and related alkaloids: structure, activity and applications. In: P. Compain, OR Martin (Ed.): Iminosugars: from synthesis to therapeutic applications. Verlag John Wiley and Sons, 2007, ISBN 0-470-03391-6 limited preview in Google Book Search
  15. ^ H. Paulsen: Carbohydrates Containing Nitrogen or Sulfur in the "Hemiacetal" Ring. In: Angew Chem Int Ed. Volume 5, 1966, pp. 495-510.
  16. ↑ N. Asano: Naturally occuring iminosugars and related alkaloids: structure, activity and applications. In: P. Compain, OR Martin (Ed.): Iminosugars: from synthesis to therapeutic applications. Publishing house John Wiley and Sons, 2007, ISBN 0-470-03391-6 , p. 7. Limited preview in the Google book search
  17. ↑ S. Inouye, T. Tsuruoka, T. Nida: The structure of nojirimycin, a piperidinose sugar antibiotic. In: Journal of Antibiotics . Volume 19, Number 6, November 1966, pp. 288-292, PMID 6013242 .