Synthesis of 8-epi-L-swainsonine, related C6 alkylated derivatives and their α-L-rhamnosidase inhibition

Yuna Shimadate; Saki Oshima; Naoto Kasamatsu; Suzuka Yamamoto; Atsumi Taguchi; Robert J. Nash; George W. J. Fleet; Takuya Okada; Naoki Toyooka; Atsushi Kato

doi:10.1016/j.tetlet.2024.155008

Synthesis of 8-epi-L-swainsonine, related C6 alkylated derivatives and their α-L-rhamnosidase inhibition

Yuna Shimadate^*, Saki Oshima, Naoto Kasamatsu, Suzuka Yamamoto, Atsumi Taguchi, Robert J. Nash, George W. J. Fleet, Takuya Okada, Naoki Toyooka, Atsushi Kato

^*Corresponding author for this work

Department of Life Sciences

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Abstract

L-Swainsonine (L-SWN) is a known inhibitor of α-L-rhamnosidase (IC₅₀ 0.13 µM), but its isomers have not been thoroughly investigated. In the present study, we focused on the 8-epi-L-SWN (6) and its analogues 9a–c and synthesized them from chiral lactam 1 as a common intermediate. 8-epi-L-SWN (6) showed moderate inhibition (IC₅₀ 87 µM), but this was about 670-fold lower than L-SWN. The introduction of a (6S)-C-methyl group into 6 significantly reduced its α-L-rhamnosidase inhibitory activity (9b: IC₅₀ 329 μM). On the other hand, among the analogues 9a–c, (6R)-C-benzyl 8-epi-L-SWN 9c was approximately 8.7 times better than (6R)-C-methyl-8-epi-L-SWN 9a. These results suggest that the α-L-rhamnosidase inhibitory activity may be further enhanced by introducing a long or bulky substituent at the C6 position of L-SWN.

Original language	English
Article number	155008
Journal	Tetrahedron Letters
Volume	139
Early online date	20 Mar 2024
DOIs	https://doi.org/10.1016/j.tetlet.2024.155008
Publication status	Published - 12 Apr 2024

Keywords

Glycosidase inhibitors
Iminosugars
Swainsonine
α-L-Rhamnosidase

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title = "Synthesis of 8-epi-L-swainsonine, related C6 alkylated derivatives and their α-L-rhamnosidase inhibition",

abstract = "L-Swainsonine (L-SWN) is a known inhibitor of α-L-rhamnosidase (IC50 0.13 µM), but its isomers have not been thoroughly investigated. In the present study, we focused on the 8-epi-L-SWN (6) and its analogues 9a–c and synthesized them from chiral lactam 1 as a common intermediate. 8-epi-L-SWN (6) showed moderate inhibition (IC50 87 µM), but this was about 670-fold lower than L-SWN. The introduction of a (6S)-C-methyl group into 6 significantly reduced its α-L-rhamnosidase inhibitory activity (9b: IC50 329 μM). On the other hand, among the analogues 9a–c, (6R)-C-benzyl 8-epi-L-SWN 9c was approximately 8.7 times better than (6R)-C-methyl-8-epi-L-SWN 9a. These results suggest that the α-L-rhamnosidase inhibitory activity may be further enhanced by introducing a long or bulky substituent at the C6 position of L-SWN.",

keywords = "Glycosidase inhibitors, Iminosugars, Swainsonine, α-L-Rhamnosidase",

author = "Yuna Shimadate and Saki Oshima and Naoto Kasamatsu and Suzuka Yamamoto and Atsumi Taguchi and Nash, {Robert J.} and Fleet, {George W. J.} and Takuya Okada and Naoki Toyooka and Atsushi Kato",

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TY - JOUR

T1 - Synthesis of 8-epi-L-swainsonine, related C6 alkylated derivatives and their α-L-rhamnosidase inhibition

AU - Shimadate, Yuna

AU - Oshima, Saki

AU - Kasamatsu, Naoto

AU - Yamamoto, Suzuka

AU - Taguchi, Atsumi

AU - Nash, Robert J.

AU - Fleet, George W. J.

AU - Okada, Takuya

AU - Toyooka, Naoki

AU - Kato, Atsushi

PY - 2024/4/12

Y1 - 2024/4/12

N2 - L-Swainsonine (L-SWN) is a known inhibitor of α-L-rhamnosidase (IC50 0.13 µM), but its isomers have not been thoroughly investigated. In the present study, we focused on the 8-epi-L-SWN (6) and its analogues 9a–c and synthesized them from chiral lactam 1 as a common intermediate. 8-epi-L-SWN (6) showed moderate inhibition (IC50 87 µM), but this was about 670-fold lower than L-SWN. The introduction of a (6S)-C-methyl group into 6 significantly reduced its α-L-rhamnosidase inhibitory activity (9b: IC50 329 μM). On the other hand, among the analogues 9a–c, (6R)-C-benzyl 8-epi-L-SWN 9c was approximately 8.7 times better than (6R)-C-methyl-8-epi-L-SWN 9a. These results suggest that the α-L-rhamnosidase inhibitory activity may be further enhanced by introducing a long or bulky substituent at the C6 position of L-SWN.

AB - L-Swainsonine (L-SWN) is a known inhibitor of α-L-rhamnosidase (IC50 0.13 µM), but its isomers have not been thoroughly investigated. In the present study, we focused on the 8-epi-L-SWN (6) and its analogues 9a–c and synthesized them from chiral lactam 1 as a common intermediate. 8-epi-L-SWN (6) showed moderate inhibition (IC50 87 µM), but this was about 670-fold lower than L-SWN. The introduction of a (6S)-C-methyl group into 6 significantly reduced its α-L-rhamnosidase inhibitory activity (9b: IC50 329 μM). On the other hand, among the analogues 9a–c, (6R)-C-benzyl 8-epi-L-SWN 9c was approximately 8.7 times better than (6R)-C-methyl-8-epi-L-SWN 9a. These results suggest that the α-L-rhamnosidase inhibitory activity may be further enhanced by introducing a long or bulky substituent at the C6 position of L-SWN.

KW - Glycosidase inhibitors

KW - Iminosugars

KW - Swainsonine

KW - α-L-Rhamnosidase

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U2 - 10.1016/j.tetlet.2024.155008

DO - 10.1016/j.tetlet.2024.155008

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AN - SCOPUS:85188505385

SN - 0040-4039

VL - 139

JO - Tetrahedron Letters

JF - Tetrahedron Letters

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ER -

Synthesis of 8-epi-L-swainsonine, related C6 alkylated derivatives and their α-L-rhamnosidase inhibition

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