Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction

Young Seub Kim; Sun Hwa Jung; Beoung Geon Park; Min Kyung Ko; Hyun Seo Jang; Kihang Choi; Ja Hyun Baik; Jiyoun Lee; Jae Kyun Lee; Ae Nim Pae; Yong Seo Cho; Sun Joon Min

doi:10.1016/j.ejmech.2012.12.033

Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction

Young Seub Kim, Sun Hwa Jung, Beoung Geon Park, Min Kyung Ko, Hyun Seo Jang, Kihang Choi, Ja Hyun Baik, Jiyoun Lee, Jae Kyun Lee, Ae Nim Pae, Yong Seo Cho, Sun Joon Min

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16 Citations (Scopus)

Abstract

Starting from quinuclidinyl oxime 1 identified by preliminary screening, a series of azacycles-containing oxime derivatives was synthesized. Their mPTP blocking activities were evaluated by a JC-1 assay, measuring the change of mitochondrial membrane potential. The inhibitory activity of nine compounds against amyloid beta-induced mPTP opening was comparable or even superior to that of piracetam. Among them, 12d effectively maintained mitochondrial function and cell viabilities on the ATP assay, the MTT assay, and the ROS assay. In addition, it exhibited favorable in vitro stability and pharmacokinetic characteristics, which hold a promise for further development of AD therapeutics.

Original language	English
Pages (from-to)	71-83
Number of pages	13
Journal	European Journal of Medicinal Chemistry
Volume	62
DOIs	https://doi.org/10.1016/j.ejmech.2012.12.033
Publication status	Published - 2013 Apr

Keywords

Alzheimer's disease
Amyloid beta
Mitochondrial permeability transition pore (mPTP)
Oxime derivatives
Pharmacokinetics

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

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10.1016/j.ejmech.2012.12.033

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@article{c75075b9efa64d8595a9d979f1afefed,

title = "Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction",

abstract = "Starting from quinuclidinyl oxime 1 identified by preliminary screening, a series of azacycles-containing oxime derivatives was synthesized. Their mPTP blocking activities were evaluated by a JC-1 assay, measuring the change of mitochondrial membrane potential. The inhibitory activity of nine compounds against amyloid beta-induced mPTP opening was comparable or even superior to that of piracetam. Among them, 12d effectively maintained mitochondrial function and cell viabilities on the ATP assay, the MTT assay, and the ROS assay. In addition, it exhibited favorable in vitro stability and pharmacokinetic characteristics, which hold a promise for further development of AD therapeutics.",

keywords = "Alzheimer's disease, Amyloid beta, Mitochondrial permeability transition pore (mPTP), Oxime derivatives, Pharmacokinetics",

author = "Kim, {Young Seub} and Jung, {Sun Hwa} and Park, {Beoung Geon} and Ko, {Min Kyung} and Jang, {Hyun Seo} and Kihang Choi and Baik, {Ja Hyun} and Jiyoun Lee and Lee, {Jae Kyun} and Pae, {Ae Nim} and Cho, {Yong Seo} and Min, {Sun Joon}",

note = "Funding Information: This research was supported by the Korea Institute of Science and Technology (KIST) and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( NRF2009-0081670 ).",

year = "2013",

month = apr,

doi = "10.1016/j.ejmech.2012.12.033",

language = "English",

volume = "62",

pages = "71--83",

journal = "European Journal of Medicinal Chemistry",

issn = "0223-5234",

publisher = "Elsevier Masson SAS",

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TY - JOUR

T1 - Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction

AU - Kim, Young Seub

AU - Jung, Sun Hwa

AU - Park, Beoung Geon

AU - Ko, Min Kyung

AU - Jang, Hyun Seo

AU - Choi, Kihang

AU - Baik, Ja Hyun

AU - Lee, Jiyoun

AU - Lee, Jae Kyun

AU - Pae, Ae Nim

AU - Cho, Yong Seo

AU - Min, Sun Joon

N1 - Funding Information: This research was supported by the Korea Institute of Science and Technology (KIST) and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology ( NRF2009-0081670 ).

PY - 2013/4

Y1 - 2013/4

N2 - Starting from quinuclidinyl oxime 1 identified by preliminary screening, a series of azacycles-containing oxime derivatives was synthesized. Their mPTP blocking activities were evaluated by a JC-1 assay, measuring the change of mitochondrial membrane potential. The inhibitory activity of nine compounds against amyloid beta-induced mPTP opening was comparable or even superior to that of piracetam. Among them, 12d effectively maintained mitochondrial function and cell viabilities on the ATP assay, the MTT assay, and the ROS assay. In addition, it exhibited favorable in vitro stability and pharmacokinetic characteristics, which hold a promise for further development of AD therapeutics.

AB - Starting from quinuclidinyl oxime 1 identified by preliminary screening, a series of azacycles-containing oxime derivatives was synthesized. Their mPTP blocking activities were evaluated by a JC-1 assay, measuring the change of mitochondrial membrane potential. The inhibitory activity of nine compounds against amyloid beta-induced mPTP opening was comparable or even superior to that of piracetam. Among them, 12d effectively maintained mitochondrial function and cell viabilities on the ATP assay, the MTT assay, and the ROS assay. In addition, it exhibited favorable in vitro stability and pharmacokinetic characteristics, which hold a promise for further development of AD therapeutics.

KW - Alzheimer's disease

KW - Amyloid beta

KW - Mitochondrial permeability transition pore (mPTP)

KW - Oxime derivatives

KW - Pharmacokinetics

UR - http://www.scopus.com/inward/record.url?scp=84872676241&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2012.12.033

DO - 10.1016/j.ejmech.2012.12.033

M3 - Article

C2 - 23353734

AN - SCOPUS:84872676241

SN - 0223-5234

VL - 62

SP - 71

EP - 83

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

ER -

Synthesis and evaluation of oxime derivatives as modulators for amyloid beta-induced mitochondrial dysfunction

Abstract

Keywords

ASJC Scopus subject areas

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