ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors

Nazmul H Bhuiyan; Michelle L Varney; Deep S Bhattacharya; William M Payne; Aaron M Mohs; Sarah A Holstein; David F Wiemer

doi:10.1016/j.bmcl.2019.126633

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ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors

Journal article

Peer reviewed

ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors

Nazmul H Bhuiyan, Michelle L Varney, Deep S Bhattacharya, William M Payne, Aaron M Mohs, Sarah A Holstein and David F Wiemer

Bioorganic & medicinal chemistry letters, Vol.29(19), pp.126633-126633

10/01/2019

DOI: 10.1016/j.bmcl.2019.126633

PMCID: PMC6936606

PMID: 31474482

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https://doi.org/10.7270/q2hd7zxrView

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Abstract

[Display omitted] The enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential therapeutic target for multiple myeloma. Malignant plasma cells produce and secrete large amounts of monoclonal protein, and inhibition of GGDPS results in disruption of protein geranylgeranylation which in turn impairs intracellular protein trafficking. Our previous work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. To explore the possibility of selective delivery of such compounds to plasma cells, new analogues with an ω-hydroxy group have been synthesized and examined for their enzymatic and cellular activity. These studies demonstrate that incorporation of the ω-hydroxy group minimally impairs GGDPS inhibitory activity. Furthermore conjugation of one of the novel ω-hydroxy GGDPS inhibitors to hyaluronic acid resulted in enhanced cellular activity. These results will allow future studies to focus on the in vivo biodistribution of HA-conjugated GGDPS inhibitors.

Bisphosphonate

GGDP synthase

Inhibition

Isoprenoid biosynthesis

Triazole

Details

Title: Subtitle: ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors
Creators: Nazmul H Bhuiyan - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, United States
Michelle L Varney - Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
Deep S Bhattacharya - Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States
William M Payne - Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States
Aaron M Mohs - Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, United States
Sarah A Holstein - Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
David F Wiemer - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, United States
Resource Type: Journal article
Publication Details: Bioorganic & medicinal chemistry letters, Vol.29(19), pp.126633-126633
DOI: 10.1016/j.bmcl.2019.126633
PMID: 31474482
PMCID: PMC6936606
NLM abbreviation: Bioorg Med Chem Lett
ISSN: 0960-894X
eISSN: 1464-3405
Publisher: Elsevier Ltd
Grant note: DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust, award: 01-224; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01CA-172070, P20 GM103480, P30 CA036727; name: Nebraska Department of Health & Human Services, award: LB-506; DOI: 10.13039/100006518, name: University of Nebraska Medical Center; DOI: 10.13039/100001797, name: PhRMA Foundation; name: Blue Waters Graduate Fellowship Program
Language: English
Date published: 10/01/2019
Academic Unit: Neuroscience and Pharmacology; Chemistry
Record Identifier: 9984216611302771

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