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.
| Original language | English (US) |
|---|---|
| Article number | 126633 |
| Journal | Bioorganic and Medicinal Chemistry Letters |
| Volume | 29 |
| Issue number | 19 |
| DOIs | |
| State | Published - Oct 1 2019 |
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Keywords
- Bisphosphonate
- GGDP synthase
- Inhibition
- Isoprenoid biosynthesis
- Triazole
ASJC Scopus subject areas
- Biochemistry
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry
Cite this
ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors. / Bhuiyan, Nazmul H.; Varney, Michelle L.; Bhattacharya, Deep S.; Payne, William M.; Mohs, Aaron M; Holstein, Sarah A; Wiemer, David F.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 29, No. 19, 126633, 01.10.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - ω-Hydroxy isoprenoid bisphosphonates as linkable GGDPS inhibitors
AU - Bhuiyan, Nazmul H.
AU - Varney, Michelle L.
AU - Bhattacharya, Deep S.
AU - Payne, William M.
AU - Mohs, Aaron M
AU - Holstein, Sarah A
AU - Wiemer, David F.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
KW - Bisphosphonate
KW - GGDP synthase
KW - Inhibition
KW - Isoprenoid biosynthesis
KW - Triazole
UR - http://www.scopus.com/inward/record.url?scp=85071396610&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85071396610&partnerID=8YFLogxK
U2 - 10.1016/j.bmcl.2019.126633
DO - 10.1016/j.bmcl.2019.126633
M3 - Article
VL - 29
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
SN - 0960-894X
IS - 19
M1 - 126633
ER -