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Bishomoisoprenoid triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase.

Abstract：

:Protein geranylgeranylation reactions are dependent on the availability of geranylgeranyl diphosphate (GGDP), which serves as the isoprenoid donor. Inhibition of GGDP synthase (GGDPS) is of interest from a drug development perspective as GGDPS inhibition results in impaired protein geranylgeranylation, which in multiple myeloma, disrupts monoclonal protein trafficking and induces apoptosis. We have recently reported a series of isoprenoid triazole bisphosphonates and have demonstrated that a 3:1 mixture of homogeranyl and homoneryl isomers potently, and in a synergistic manner, inhibits GGDPS. We now present the synthesis and biological evaluation of a novel series of bishomoisoprenoid triazoles which furthers our understanding of the structure-function relationship of this class. These studies demonstrate the importance of chain length and olefin stereochemistry on inhibitory activity.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Wills VS,Metzger JI,Allen C,Varney ML,Wiemer DF,Holstein SA

doi

10.1016/j.bmc.2017.02.066

subject

Has Abstract

pub_date

2017-04-15 00:00:00

pages

2437-2444

issue

8

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(17)30193-1

journal_volume

25

pub_type

杂志文章

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