N-oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation

Xiang Zhou; Ella J. Born; Cheryl Allen; Sarah A. Holstein; David F. Wiemer

doi:10.1016/j.bmcl.2015.04.021

N-oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation

Xiang Zhou, Ella J. Born, Cheryl Allen, Sarah A. Holstein, David F. Wiemer

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Abstract The N-oxide derivatives of [2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid (or PEHPC) and [2-(3-pyridinyl)-1-ethylidene-1,1-phosphonocarboxylic acid (or PEPC) have been prepared and evaluated for their activity against several enzymes which utilize isoprenoids. The parent pyridines are known inhibitors of GGTase II, but the N-oxide derivatives show no improvement in biological activity in assays with the isolated enzyme. However, the PEHPC N-oxide did induce significant accumulation of intracellular light chain in myeloma cells, consistent with inhibition of Rab geranylgeranylation.

Original language	English (US)
Article number	22604
Pages (from-to)	2331-2334
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	25
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2015.04.021
State	Published - Jun 1 2015
Externally published	Yes

Keywords

Apoptosis
Bioassay
GGTase II
Myeloma
Pyridyl N-oxides
Rab GGTase

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2015.04.021

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@article{e117e2a67b634b6fb0ceb138da2f7658,

title = "N-oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation",

abstract = "Abstract The N-oxide derivatives of [2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid (or PEHPC) and [2-(3-pyridinyl)-1-ethylidene-1,1-phosphonocarboxylic acid (or PEPC) have been prepared and evaluated for their activity against several enzymes which utilize isoprenoids. The parent pyridines are known inhibitors of GGTase II, but the N-oxide derivatives show no improvement in biological activity in assays with the isolated enzyme. However, the PEHPC N-oxide did induce significant accumulation of intracellular light chain in myeloma cells, consistent with inhibition of Rab geranylgeranylation.",

keywords = "Apoptosis, Bioassay, GGTase II, Myeloma, Pyridyl N-oxides, Rab GGTase",

author = "Xiang Zhou and Born, {Ella J.} and Cheryl Allen and Holstein, {Sarah A.} and Wiemer, {David F.}",

year = "2015",

month = jun,

day = "1",

doi = "10.1016/j.bmcl.2015.04.021",

language = "English (US)",

volume = "25",

pages = "2331--2334",

journal = "Bioorganic and Medicinal Chemistry Letters",

issn = "0960-894X",

publisher = "Elsevier Ltd",

number = "11",

}

TY - JOUR

T1 - N-oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation

AU - Zhou, Xiang

AU - Born, Ella J.

AU - Allen, Cheryl

AU - Holstein, Sarah A.

AU - Wiemer, David F.

PY - 2015/6/1

Y1 - 2015/6/1

N2 - Abstract The N-oxide derivatives of [2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid (or PEHPC) and [2-(3-pyridinyl)-1-ethylidene-1,1-phosphonocarboxylic acid (or PEPC) have been prepared and evaluated for their activity against several enzymes which utilize isoprenoids. The parent pyridines are known inhibitors of GGTase II, but the N-oxide derivatives show no improvement in biological activity in assays with the isolated enzyme. However, the PEHPC N-oxide did induce significant accumulation of intracellular light chain in myeloma cells, consistent with inhibition of Rab geranylgeranylation.

AB - Abstract The N-oxide derivatives of [2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid (or PEHPC) and [2-(3-pyridinyl)-1-ethylidene-1,1-phosphonocarboxylic acid (or PEPC) have been prepared and evaluated for their activity against several enzymes which utilize isoprenoids. The parent pyridines are known inhibitors of GGTase II, but the N-oxide derivatives show no improvement in biological activity in assays with the isolated enzyme. However, the PEHPC N-oxide did induce significant accumulation of intracellular light chain in myeloma cells, consistent with inhibition of Rab geranylgeranylation.

KW - Apoptosis

KW - Bioassay

KW - GGTase II

KW - Myeloma

KW - Pyridyl N-oxides

KW - Rab GGTase

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U2 - 10.1016/j.bmcl.2015.04.021

DO - 10.1016/j.bmcl.2015.04.021

M3 - Article

C2 - 25935643

AN - SCOPUS:84937760349

SN - 0960-894X

VL - 25

SP - 2331

EP - 2334

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 11

M1 - 22604

ER -

N-oxide derivatives of 3-(3-pyridyl)-2-phosphonopropanoic acids as potential inhibitors of Rab geranylgeranylation

Abstract

Keywords

ASJC Scopus subject areas

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