ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors

doi:10.1016/j.bmcl.2019.126633

Bioorganic & Medicinal Chemistry Letters

Volume 29, Issue 19, 1 October 2019, 126633

https://doi.org/10.1016/j.bmcl.2019.126633 Get rights and content

Abstract

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.

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Acknowledgements

We thank Jack Neal for his assistance with preparation of some of the synthetic intermediates. This project was supported in part by the Roy J. Carver Charitable Trust (01-224 to DFW), the National Institutes of Health (R01CA-172070 to SAH, P20 GM103480 and P30 CA036727), and the Nebraska Department of Health & Human Services (LB-506). DB was supported through a University of Nebraska Medical Center Program of Excellence Assistantship, and WMP was supported by fellowships from the PhRMA

References (54)

S.A. Holstein et al.
Isoprenoid biosynthetic pathway inhibition disrupts monoclonal protein secretion and induces the unfolded protein response pathway in multiple myeloma cells
Leuk Res
(2011)
L.W. Shull et al.
Synthesis and biological activity of isoprenoid bisphosphonates
Bioorg Med Chem
(2006)
X. Zhou et al.
Geranyl and neryl triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase
Bioorg Med Chem
(2014)
R.A. Matthiesen et al.
alpha-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors
Bioorg Med Chem
(2018)
K.Y. Choi et al.
Theranostic nanoparticles based on PEGylated hyaluronic acid for the diagnosis, therapy and monitoring of colon cancer
Biomaterials
(2012)
J.J. Souchek et al.
Hyaluronic acid formulation of near infrared fluorophores optimizes surgical imaging in a prostate tumor xenograft
Acta Biomater
(2018)
S. Ganesh et al.
Hyaluronic acid based self-assembling nanosystems for CD44 target mediated siRNA delivery to solid tumors
Biomaterials
(2013)
Z. Gu et al.
Hyaluronic acid shell and disulfide-crosslinked core micelles for in vivo targeted delivery of bortezomib for the treatment of multiple myeloma
Acta Biomater
(2018)
M.B. Reardon et al.
Long-range reactivity modulations in geranyl chloride derivatives
J Org Chem
(2016)
A. Padwa et al.
Intramolecular O-H insertion reaction of azido substituted diazoesters and its relevance to the mechanism of the allylic azide rearrangement
Tetrahedron Lett
(1997)

X. Zhou et al.

Triazole-based inhibitors of geranylgeranyltransferase II

Bioorg Med Chem Lett

(2013)

C.E. McKenna et al.

Facile dealkylation of phosphonic acid dialkyl esters by bromotrimethylsilane

Tetrahedron Lett

(1977)

R.A. Matthiesen et al.

Stereoselective synthesis of homoneryl and homogeranyl triazole bisphosphonates

J Org Chem

(2016)

H.J. Huang et al.

Synthesis of moenocinol and its analogs using BT-sulfone in Julia-Kocienski olefination

Tetrahedron Lett

(2007)

S.S. Kelkar et al.

Near infrared fluorescent nanoparticles based on hyaluronic acid: self-assembly, optical properties, and cell interaction

Acta Biomater

(2016)

T. Fukami et al.

The emerging role of human esterases

Drug Metab Pharmacokinet

(2012)

E.M. Davis et al.

Cyclization enzymes in the biosynthesis of monoterpenes, sesquiterpenes, and diterpenes

A.J. Wiemer et al.

Geranylgeranyl diphosphate synthase: an emerging therapeutic target

Clin Pharmacol Ther

(2011)

C.D. Lawson et al.

Rho GTPase signaling complexes in cell migration and invasion

J Cell Biol

(2018)

B.L. Grosshans et al.

Rabs and their effectors: achieving specificity in membrane traffic

PNAS

(2006)

R. Chou et al.

Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US preventive services task force

JAMA

(2016)

S. Cremers et al.

Pharmacology of bisphosphonates

Br J Clin Pharmacol

(2019)

M. Thurnher et al.

Novel aspects of mevalonate pathway inhibitors as antitumor agents

Clin Cancer Res

(2012)

M. Schachter

Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update

Fundam Clin Pharmacol

(2005)

H.Y. Pan et al.

Comparative pharmacokinetics and pharmacodynamics of pravastatin and lovastatin

J Clin Pharmacol

(1990)

T. Chen et al.

Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases

J Clin Pharmacol

(2002)

S.L. Haney et al.

Recent advances in the development of mammalian geranylgeranyl diphosphate synthase inhibitors

Molecules

(2017)

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α-Amino bisphosphonate triazoles serve as GGDPS inhibitors
2024, Bioorganic and Medicinal Chemistry Letters
Depletion of cellular levels of geranylgeranyl diphosphate by inhibition of the enzyme geranylgeranyl diphosphate synthase (GGDPS) is a potential strategy for disruption of protein transport by limiting the geranylgeranylation of the Rab proteins that regulate intracellular trafficking. As such, there is interest in the development of GGDPS inhibitors for the treatment of malignancies characterized by abnormal protein production, including multiple myeloma. Our previous work has explored the structure-function relationship of a series of isoprenoid triazole bisphosphonate-based GGDPS inhibitors, with modifications having impact on enzymatic, cellular and in vivo activities. We have synthesized a new series of α-amino bisphosphonates to understand the impact of modifying the alpha position with a moiety that is potentially linkable to other agents. Bioassays evaluating the enzymatic and cellular activities of these compounds demonstrate that incorporation of the α-amino group affords compounds with GGDPS inhibitory activity which is modulated by isoprenoid tail chain length and olefin stereochemistry. These studies provide further insight into the complexity of the structure-function relationship and will enable future efforts focused on tumor-specific drug delivery.
Impact of α-modifications on the activity of triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors
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Citation Excerpt :
This is in contrast to an analogue in which the hydroxyl group was incorporated at the ω-position, which led to an approximately 20-fold decrease in potency (relative to 1).21 However, this ω-hydroxy derivative was of interest because of its ability to be linked to hyaluronic acid and enhance drug delivery,21 thus future studies will focus on determining whether the α-hydroxy derivative 37, as well as other potentially linkable derivatives such as the α-aminomethylene compound 17, can be conjugated to hyaluronic acid and alter not only uptake into myeloma cells but also in vivo biodistribution patterns. Biological activity in the cell-based assays is dependent on several factors beyond binding to the target enzyme, including membrane permeability if cell entry occurs by passive diffusion or compatibility with an isoprenoid transporter if cell entry occurs via an active system.
Agents that inhibit the enzyme geranylgeranyl diphosphate synthase (GGDPS) have anti-cancer activity and our prior studies have investigated the structure-function relationship for a family of isoprenoid triazole bisphosphonates as GGDPS inhibitors. To further explore this structure-function relationship, a series of novel α-modified triazole phosphonates was prepared and evaluated for activity as GGDPS inhibitors in enzyme and cell-based assays. These studies revealed flexibility at the α position of the bisphosphonate derivatives with respect to being able to accommodate a variety of substituents without significantly affecting potency compared to the parent unsubstituted inhibitor. However, the monophosphonate derivatives lacked activity. These studies further our understanding of the structure-function relationship of the triazole-based GGDPS inhibitors and lay the foundation for future studies evaluating the impact of α-modifications on in vivo activity.
Amides as bioisosteres of triazole-based geranylgeranyl diphosphate synthase inhibitors
2020, Bioorganic and Medicinal Chemistry
Citation Excerpt :
During the course of our efforts to develop GGDPS inhibitors, we reported a series of di- and monoalkyl isoprenoid bisphosphonates that selectively inhibit GGDPS over other enzymes in the IBP.12–17 Subsequently, our efforts have focused on the development of triazole-based GGDPS inhibitors,18–24 prepared using “click” chemistry25 to introduce the isoprenoid unit. One benefit of the click strategy is that it allows reasonably efficient preparation of groups of compounds from a common intermediate.
Geranylgeranyl diphosphate synthase (GGDPS) inhibitors are of potential therapeutic interest as a consequence of their activity against the bone marrow cancer multiple myeloma. A series of bisphosphonates linked to an isoprenoid tail through an amide linkage has been prepared and tested for the ability to inhibit GGDPS in enzyme and cell-based assays. The amides were designed as analogues to triazole-based GGDPS inhibitors. Several of the new compounds show GGDPS inhibitory activity in both enzyme and cell assays, with potency dependent on chain length and olefin stereochemistry.
Structural insight into geranylgeranyl diphosphate synthase (GGDPS) for cancer therapy
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Geranylgeranyl diphosphate synthase inhibitor and proteasome inhibitor combination therapy in multiple myeloma
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Hydroxy- and Amino-Phosphonates and -Bisphosphonates: Synthetic Methods and Their Biological Applications
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ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors

Abstract

Graphical abstract

Section snippets

Acknowledgements

Leuk Res

Bioorg Med Chem

Bioorg Med Chem

Bioorg Med Chem

Biomaterials

Acta Biomater

Biomaterials

Acta Biomater

J Org Chem

Tetrahedron Lett

Bioorg Med Chem Lett

Tetrahedron Lett

J Org Chem

Tetrahedron Lett

Acta Biomater

Drug Metab Pharmacokinet

Cyclization enzymes in the biosynthesis of monoterpenes, sesquiterpenes, and diterpenes

Geranylgeranyl diphosphate synthase: an emerging therapeutic target

Clin Pharmacol Ther

Rho GTPase signaling complexes in cell migration and invasion

J Cell Biol

Rabs and their effectors: achieving specificity in membrane traffic

PNAS

Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US preventive services task force

JAMA

Pharmacology of bisphosphonates

Br J Clin Pharmacol

Novel aspects of mevalonate pathway inhibitors as antitumor agents

Clin Cancer Res

Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update

Fundam Clin Pharmacol

Comparative pharmacokinetics and pharmacodynamics of pravastatin and lovastatin

J Clin Pharmacol

Pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with bone metastases

J Clin Pharmacol

Recent advances in the development of mammalian geranylgeranyl diphosphate synthase inhibitors

Molecules