Synthesis of acyloxymethyl ester prodrugs of the transferable protein farnesyl transferase substrate farnesyl methylenediphosphonate

Jerry M. Troutman; Kareem A.H. Chehade; Katarzyna Kiegiel; Douglas A. Andres; H. Peter Spielmann

doi:10.1016/j.bmcl.2004.07.017

Synthesis of acyloxymethyl ester prodrugs of the transferable protein farnesyl transferase substrate farnesyl methylenediphosphonate

Jerry M. Troutman
, Kareem A.H. Chehade
, Katarzyna Kiegiel
, Douglas A. Andres
, H. Peter Spielmann

Producción científica: Article › revisión exhaustiva

18 Citas (Scopus)

Resumen

Three isoprenoid diphosphate analogues of farnesyl diphosphate (FPP) where the diphosphate has been replaced by methylene diphosphonate and the negative charges masked by frangible pivaloyloxymethyl (POM) esters were prepared. Farnesyl methylenediphosphonate is a sub-micromolar substrate for protein farnesyl transferase. The tripivaloyloxymethyl esters of isoprenoid methylenediphosphonate have significantly increased lipophilicity and may act as important farnesyl diphosphate prodrugs.

Idioma original	English
Páginas (desde-hasta)	4979-4982
Número de páginas	4
Publicación	Bioorganic and Medicinal Chemistry Letters
Volumen	14
N.º	19
DOI	https://doi.org/10.1016/j.bmcl.2004.07.017
Estado	Published - oct 4 2004

Nota bibliográfica

Funding Information:
This work was supported in part by the Kentucky Lung Cancer Research Program (to H.P.S. and D.A.A.), the National Institutes of Health (GM66152-01 to H.P.S.), and the NMR instruments used in this work were obtained with support from NSF CRIF Grant No. CHE-9974810. We thank Dr. Carol Fierke and Jennifer Pickett for the gift of rat protein farnesyltransferase.

Financiación

This work was supported in part by the Kentucky Lung Cancer Research Program (to H.P.S. and D.A.A.), the National Institutes of Health (GM66152-01 to H.P.S.), and the NMR instruments used in this work were obtained with support from NSF CRIF Grant No. CHE-9974810. We thank Dr. Carol Fierke and Jennifer Pickett for the gift of rat protein farnesyltransferase.

Financiadores	Número del financiador
Kentucky Lung Cancer Research Program
National Science Foundation Arctic Social Science Program	CHE-9974810
National Institutes of Health (NIH)	GM66152-01
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	R01GM066152

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.2004.07.017

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@article{79a1cdb3338c469a8a2026ba9df261d3,

title = "Synthesis of acyloxymethyl ester prodrugs of the transferable protein farnesyl transferase substrate farnesyl methylenediphosphonate",

abstract = "Three isoprenoid diphosphate analogues of farnesyl diphosphate (FPP) where the diphosphate has been replaced by methylene diphosphonate and the negative charges masked by frangible pivaloyloxymethyl (POM) esters were prepared. Farnesyl methylenediphosphonate is a sub-micromolar substrate for protein farnesyl transferase. The tripivaloyloxymethyl esters of isoprenoid methylenediphosphonate have significantly increased lipophilicity and may act as important farnesyl diphosphate prodrugs.",

keywords = "Bisphosphonates, Farnesylation, Prodrugs",

author = "Troutman, \{Jerry M.\} and Chehade, \{Kareem A.H.\} and Katarzyna Kiegiel and Andres, \{Douglas A.\} and Spielmann, \{H. Peter\}",

note = "Funding Information: This work was supported in part by the Kentucky Lung Cancer Research Program (to H.P.S. and D.A.A.), the National Institutes of Health (GM66152-01 to H.P.S.), and the NMR instruments used in this work were obtained with support from NSF CRIF Grant No. CHE-9974810. We thank Dr. Carol Fierke and Jennifer Pickett for the gift of rat protein farnesyltransferase.",

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doi = "10.1016/j.bmcl.2004.07.017",

language = "English",

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TY - JOUR

T1 - Synthesis of acyloxymethyl ester prodrugs of the transferable protein farnesyl transferase substrate farnesyl methylenediphosphonate

AU - Troutman, Jerry M.

AU - Chehade, Kareem A.H.

AU - Kiegiel, Katarzyna

AU - Andres, Douglas A.

AU - Spielmann, H. Peter

N1 - Funding Information: This work was supported in part by the Kentucky Lung Cancer Research Program (to H.P.S. and D.A.A.), the National Institutes of Health (GM66152-01 to H.P.S.), and the NMR instruments used in this work were obtained with support from NSF CRIF Grant No. CHE-9974810. We thank Dr. Carol Fierke and Jennifer Pickett for the gift of rat protein farnesyltransferase.

PY - 2004/10/4

Y1 - 2004/10/4

N2 - Three isoprenoid diphosphate analogues of farnesyl diphosphate (FPP) where the diphosphate has been replaced by methylene diphosphonate and the negative charges masked by frangible pivaloyloxymethyl (POM) esters were prepared. Farnesyl methylenediphosphonate is a sub-micromolar substrate for protein farnesyl transferase. The tripivaloyloxymethyl esters of isoprenoid methylenediphosphonate have significantly increased lipophilicity and may act as important farnesyl diphosphate prodrugs.

AB - Three isoprenoid diphosphate analogues of farnesyl diphosphate (FPP) where the diphosphate has been replaced by methylene diphosphonate and the negative charges masked by frangible pivaloyloxymethyl (POM) esters were prepared. Farnesyl methylenediphosphonate is a sub-micromolar substrate for protein farnesyl transferase. The tripivaloyloxymethyl esters of isoprenoid methylenediphosphonate have significantly increased lipophilicity and may act as important farnesyl diphosphate prodrugs.

KW - Bisphosphonates

KW - Farnesylation

KW - Prodrugs

UR - https://www.scopus.com/pages/publications/4444292598

UR - https://www.scopus.com/pages/publications/4444292598#tab=citedBy

U2 - 10.1016/j.bmcl.2004.07.017

DO - 10.1016/j.bmcl.2004.07.017

M3 - Article

C2 - 15341963

AN - SCOPUS:4444292598

SN - 0960-894X

VL - 14

SP - 4979

EP - 4982

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 19

ER -

Synthesis of acyloxymethyl ester prodrugs of the transferable protein farnesyl transferase substrate farnesyl methylenediphosphonate

Resumen

Nota bibliográfica

Financiación

ASJC Scopus subject areas

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