Development of non-degradable analogue similar to glycolipid

December 24, 2020

Organic synthesis approach to resolve long-standing issues involved in molecular design

A joint research group of RIKEN Cluster for Pioneering Research, RIKEN CSRS, and Kyushu University has succeeded in development of an analogue (similar compound) of ganglioside GM3, a type of glycosphingolipids deeply involved in cellular functions. The developed analogue has almost the same physical properties and structure as GM3, but is non-degradable with enzymes in the living body. In addition, the analogue has a higher biological activity than that of GM3.

Since carbohydrate chains are degraded and reconstructed (metabolized) by activity of enzymes in the living body, their functions are easily changed. This serves as a barrier for elucidation of their functions.

In this study, the joint research group chemically synthesized four types of analogues including a CHF-linked type (with R- and S- isomers) where the oxygen atom (O) of the glycosidic linkage in GM3 is replaced with a carbon atom (C) having one fluorine atom (F) being attached. Results from a comparison of biological activities against cancer cell growth showed that the CHF-linked analogue has a higher activity. In particular, S-isomer of this analogue was found to have a 1.6-fold greater activity compared to GM3. In addition, the S-isomer analogue was demonstrated to be confined to one active GM3 conformation, synergistically enhancing the biological activity with resistance to degradation.

The study results may contribute to functional elucidation of carbohydrate chains (glycoconjugates) and middle molecule drug discovery.

Original article
JACS Au  doi:10.1021/jacsau.0c00058
G. Hirai, M. Kato, H. Koshino, E. Nishizawa, K. Oonuma, E. Ota, T. Watanabe, D. Hashizume, Y. Tamura, M. Okada, T. Miyagi, M. Sodeoka,
"Ganglioside GM3 Analogues Containing Monofluoromethylene-linked Sialoside: Synthesis, Stereochemical Effects, Conformational Behavior, and Biological Activities".
Go Hirai; Visiting Scientist
Mikiko Sodeoka; Group Director
Catalysis and Integrated Research Group
Hiroyuki Koshino; Unit Leader
Molecular Structure Characterization Unit