TY - JOUR
T1 - Design, synthesis and conformation-activity relationship analysis of LNA/BNA-type 5′-O-aminoribosyluridine as MraY inhibitors
AU - Kusaka, Shintaro
AU - Yamamoto, Kazuki
AU - Shinohara, Motoko
AU - Minato, Yusuke
AU - Ichikawa, Satoshi
N1 - Funding Information:
We are thankful Dr. K. Nishiguchi and Dr. S. Arioka (Shionogi Co., Ltd.) for MraY expression and purification. This research was supported in part by JSPS KAKENHI Grant-in-Aid for Scientific Research (B) (Grant Number 19H03345 to S.I.), Grant-in Aid for Scientific Research on Innovative Areas “Frontier Research on Chemical Communications” (No 20H04757 to S.I.), Agency for Medical Research and Development (AMED) (No JP21fk0108128, JP21fk0108607, and JP21nk0101566 to Y.M), and was partly supported by Hokkaido University, Global Facility Center (GFC), Pharma Science Open Unit (PSOU), funded by MEXT under “Support Program for Implementation of New Equipment Sharing System”, Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED (No JP18am0101093j000).
Funding Information:
We are thankful Dr. K. Nishiguchi and Dr. S. Arioka (Shionogi Co. Ltd.) for MraY expression and purification. This research was supported in part by JSPS KAKENHI Grant-in-Aid for Scientific Research (B) (Grant Number 19H03345 to S.I.), Grant-in Aid for Scientific Research on Innovative Areas ?Frontier Research on Chemical Communications? (No 20H04757 to S.I.), Agency for Medical Research and Development (AMED) (No JP21fk0108128, JP21fk0108607, and JP21nk0101566 to Y.M), and was partly supported by Hokkaido University, Global Facility Center (GFC), Pharma Science Open Unit (PSOU), funded by MEXT under ?Support Program for Implementation of New Equipment Sharing System?, Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED (No JP18am0101093j000).
Publisher Copyright:
© 2022 Elsevier Ltd
PY - 2022/7/1
Y1 - 2022/7/1
N2 - It is important to understand and control the biologically active conformation in medicinal chemistry. Muraymycins and caprazamycins, which are strong inhibitors of MraY, are promising antibacterial agents with a novel mode of action. Focusing on a sugar puckering and a dihedral angle ϕ of the uridine moiety of these natural products, LNA/BNA-type 5′-O-aminoribosyluridine analogues, whose puckering of the ribose moiety are completely restricted to the N-type, were designed and synthesized as simplified MraY inhibitors. Their conformation-activity relationship was further investigated in details. The conformation-activity relationship analysis investigated in this study could be a general guideline for simplification and rational drug design of MraY inhibitory nucleoside natural products.
AB - It is important to understand and control the biologically active conformation in medicinal chemistry. Muraymycins and caprazamycins, which are strong inhibitors of MraY, are promising antibacterial agents with a novel mode of action. Focusing on a sugar puckering and a dihedral angle ϕ of the uridine moiety of these natural products, LNA/BNA-type 5′-O-aminoribosyluridine analogues, whose puckering of the ribose moiety are completely restricted to the N-type, were designed and synthesized as simplified MraY inhibitors. Their conformation-activity relationship was further investigated in details. The conformation-activity relationship analysis investigated in this study could be a general guideline for simplification and rational drug design of MraY inhibitory nucleoside natural products.
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U2 - 10.1016/j.bmc.2022.116744
DO - 10.1016/j.bmc.2022.116744
M3 - Article
C2 - 35500521
AN - SCOPUS:85129468629
VL - 65
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
M1 - 116744
ER -