Design and synthesis of non-hydrolyzable homoisoprenoid α-monofluorophosphonate inhibitors of PPAPDC family integral membrane lipid phosphatases

Thangaiah Subramanian; Hongmei Ren; Karunai Leela Subramanian; Manjula Sunkara; Fredrick O. Onono; Andrew J. Morris; H. Peter Spielmann

doi:10.1016/j.bmcl.2014.08.013

Design and synthesis of non-hydrolyzable homoisoprenoid α-monofluorophosphonate inhibitors of PPAPDC family integral membrane lipid phosphatases

Thangaiah Subramanian, Hongmei Ren, Karunai Leela Subramanian, Manjula Sunkara, Fredrick O. Onono, Andrew J. Morris, H. Peter Spielmann

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

3 Scopus citations

Abstract

An efficient, diversity oriented synthesis of homoisoprenoid α-monofluorophosphonates utilizing electrophilic fluorination is presented along with their activity as inhibitors of PPAPDC2 family integral membrane lipid phosphatases. These novel phosphatase-resistant analogues of isoprenoid monophosphates are a platform for further structure-activity relationship studies and provide access to other isoprenoid family members where the phosphate ester oxygen is replaced by a α-monofluoromethylene moiety.

Original language	English
Pages (from-to)	4414-4417
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	24
Issue number	18
DOIs	https://doi.org/10.1016/j.bmcl.2014.08.013
State	Published - Sep 15 2014

Bibliographical note

Funding Information:
We thank Drs. Jing Chen and Haining Zhu for assistance obtaining some of the mass spectra. This work was supported by NIH grants R01 GM66152 to H.P.S., R01 GM50388 , P20 GM103527 and with resources provided by the Lexington Veterans Affairs Medical Center to A.J.M.

Publisher Copyright:
© 2014 Elsevier Ltd. All rights reserved.

Keywords

Farnesyl diphosphate
Isoprenol
Mevalonate pathway
Phosphatase inhibitor
Phosphonate

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.2014.08.013

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title = "Design and synthesis of non-hydrolyzable homoisoprenoid α-monofluorophosphonate inhibitors of PPAPDC family integral membrane lipid phosphatases",

abstract = "An efficient, diversity oriented synthesis of homoisoprenoid α-monofluorophosphonates utilizing electrophilic fluorination is presented along with their activity as inhibitors of PPAPDC2 family integral membrane lipid phosphatases. These novel phosphatase-resistant analogues of isoprenoid monophosphates are a platform for further structure-activity relationship studies and provide access to other isoprenoid family members where the phosphate ester oxygen is replaced by a α-monofluoromethylene moiety.",

keywords = "Farnesyl diphosphate, Isoprenol, Mevalonate pathway, Phosphatase inhibitor, Phosphonate",

author = "Thangaiah Subramanian and Hongmei Ren and Subramanian, {Karunai Leela} and Manjula Sunkara and Onono, {Fredrick O.} and Morris, {Andrew J.} and Spielmann, {H. Peter}",

note = "Funding Information: We thank Drs. Jing Chen and Haining Zhu for assistance obtaining some of the mass spectra. This work was supported by NIH grants R01 GM66152 to H.P.S., R01 GM50388 , P20 GM103527 and with resources provided by the Lexington Veterans Affairs Medical Center to A.J.M. Publisher Copyright: {\textcopyright} 2014 Elsevier Ltd. All rights reserved.",

year = "2014",

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day = "15",

doi = "10.1016/j.bmcl.2014.08.013",

language = "English",

volume = "24",

pages = "4414--4417",

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Design and synthesis of non-hydrolyzable homoisoprenoid α-monofluorophosphonate inhibitors of PPAPDC family integral membrane lipid phosphatases. / Subramanian, Thangaiah; Ren, Hongmei; Subramanian, Karunai Leela et al.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 24, No. 18, 15.09.2014, p. 4414-4417.

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

TY - JOUR

T1 - Design and synthesis of non-hydrolyzable homoisoprenoid α-monofluorophosphonate inhibitors of PPAPDC family integral membrane lipid phosphatases

AU - Subramanian, Thangaiah

AU - Ren, Hongmei

AU - Subramanian, Karunai Leela

AU - Sunkara, Manjula

AU - Onono, Fredrick O.

AU - Morris, Andrew J.

AU - Spielmann, H. Peter

N1 - Funding Information: We thank Drs. Jing Chen and Haining Zhu for assistance obtaining some of the mass spectra. This work was supported by NIH grants R01 GM66152 to H.P.S., R01 GM50388 , P20 GM103527 and with resources provided by the Lexington Veterans Affairs Medical Center to A.J.M. Publisher Copyright: © 2014 Elsevier Ltd. All rights reserved.

PY - 2014/9/15

Y1 - 2014/9/15

N2 - An efficient, diversity oriented synthesis of homoisoprenoid α-monofluorophosphonates utilizing electrophilic fluorination is presented along with their activity as inhibitors of PPAPDC2 family integral membrane lipid phosphatases. These novel phosphatase-resistant analogues of isoprenoid monophosphates are a platform for further structure-activity relationship studies and provide access to other isoprenoid family members where the phosphate ester oxygen is replaced by a α-monofluoromethylene moiety.

AB - An efficient, diversity oriented synthesis of homoisoprenoid α-monofluorophosphonates utilizing electrophilic fluorination is presented along with their activity as inhibitors of PPAPDC2 family integral membrane lipid phosphatases. These novel phosphatase-resistant analogues of isoprenoid monophosphates are a platform for further structure-activity relationship studies and provide access to other isoprenoid family members where the phosphate ester oxygen is replaced by a α-monofluoromethylene moiety.

KW - Farnesyl diphosphate

KW - Isoprenol

KW - Mevalonate pathway

KW - Phosphatase inhibitor

KW - Phosphonate

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Design and synthesis of non-hydrolyzable homoisoprenoid α-monofluorophosphonate inhibitors of PPAPDC family integral membrane lipid phosphatases

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

Access to Document

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