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A new motif for inhibitors of geranylgeranyl diphosphate synthase.

Abstract：

:The enzyme geranylgeranyl diphosphate synthase (GGDPS) is believed to receive the substrate farnesyl diphosphate through one lipophilic channel and release the product geranylgeranyl diphosphate through another. Bisphosphonates with two isoprenoid chains positioned on the α-carbon have proven to be effective inhibitors of this enzyme. Now a new motif has been prepared with one isoprenoid chain on the α-carbon, a second included as a phosphonate ester, and the potential for a third at the α-carbon. The pivaloyloxymethyl prodrugs of several compounds based on this motif have been prepared and the resulting compounds have been tested for their ability to disrupt protein geranylgeranylation and induce cytotoxicity in myeloma cells. The initial biological studies reveal activity consistent with GGDPS inhibition, and demonstrate a structure-function relationship which is dependent on the nature of the alkyl group at the α-carbon.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Foust BJ,Allen C,Holstein SA,Wiemer DF

doi

10.1016/j.bmc.2016.06.019

subject

Has Abstract

pub_date

2016-08-15 00:00:00

pages

3734-41

issue

16

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(16)30442-4

journal_volume

24

pub_type

杂志文章

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