α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors

Robert A Matthiesen; Michelle L Varney; Pauline C Xu; Alex S Rier; David F Wiemer; Sarah A Holstein

doi:10.1016/j.bmc.2017.10.023

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α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors

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α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors

Robert A Matthiesen, Michelle L Varney, Pauline C Xu, Alex S Rier, David F Wiemer and Sarah A Holstein

Bioorganic & medicinal chemistry, Vol.26(2), pp.376-385

01/15/2018

DOI: 10.1016/j.bmc.2017.10.023

PMCID: PMC5752576

PMID: 29248353

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Abstract

[Display omitted] Disruption of protein geranylgeranylation via inhibition of geranylgeranyl diphosphate synthase (GGDPS) represents a novel therapeutic strategy for a variety of malignancies, especially those characterized by excessive protein secretion such as multiple myeloma. Our work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. Here we present the synthesis and biological evaluation of a new series of isoprenoid triazoles modified by incorporation of a methyl group at the α-carbon. These studies reveal that incorporation of an α-methyl substituent enhances the potency of these compounds as GGDPS inhibitors, and, in the case of the homogeranyl/homoneryl series, abrogates the effects of olefin stereochemistry on inhibitory activity. The incorporation of the methyl group allowed preparation of a POM-prodrug, which displayed a 10-fold increase in cellular activity compared to the corresponding salt. These studies form the basis for future preclinical studies investigating the anti-myeloma activity of these novel α-methyl triazole bisphosphonates.

Triazole

Bisphosphonate

Inhibition

GGDP synthase

Isoprenoid biosynthesis

Details

Title: Subtitle: α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors
Creators: Robert A Matthiesen - 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
Pauline C Xu - College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
Alex S Rier - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, United States
David F Wiemer - Department of Chemistry, University of Iowa, Iowa City, IA 52242-1294, United States
Sarah A Holstein - Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
Resource Type: Journal article
Publication Details: Bioorganic & medicinal chemistry, Vol.26(2), pp.376-385
DOI: 10.1016/j.bmc.2017.10.023
PMID: 29248353
PMCID: PMC5752576
NLM abbreviation: Bioorg Med Chem
ISSN: 0968-0896
eISSN: 1464-3391
Publisher: Elsevier Ltd
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: R01CA-172070; DOI: 10.13039/100001024, name: Roy J. Carver Charitable Trust, award: R01CA-172070
Language: English
Date published: 01/15/2018
Academic Unit: Anesthesia; Neuroscience and Pharmacology; Chemistry
Record Identifier: 9983985849802771

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