Amides as bioisosteres of triazole-based geranylgeranyl diphosphate synthase inhibitors

Daniel B. Goetz; Michelle L. Varney; David F. Wiemer; Sarah A. Holstein

doi:10.1016/j.bmc.2020.115604

Amides as bioisosteres of triazole-based geranylgeranyl diphosphate synthase inhibitors

Daniel B. Goetz, Michelle L. Varney, David F. Wiemer, Sarah A. Holstein

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

Abstract

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.

Original language	English (US)
Article number	115604
Journal	Bioorganic and Medicinal Chemistry
Volume	28
Issue number	16
DOIs	https://doi.org/10.1016/j.bmc.2020.115604
State	Published - Aug 15 2020

Keywords

Amide
Bioisostere
Bisphosphonate
Geranylgeranyl diphosphate synthase
Inhibition
Isoprenoid biosynthesis
Myeloma
Triazole

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmc.2020.115604

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title = "Amides as bioisosteres of triazole-based geranylgeranyl diphosphate synthase inhibitors",

abstract = "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.",

keywords = "Amide, Bioisostere, Bisphosphonate, Geranylgeranyl diphosphate synthase, Inhibition, Isoprenoid biosynthesis, Myeloma, Triazole",

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language = "English (US)",

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AU - Goetz, Daniel B.

AU - Varney, Michelle L.

AU - Wiemer, David F.

AU - Holstein, Sarah A.

PY - 2020/8/15

Y1 - 2020/8/15

N2 - 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.

AB - 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.

KW - Amide

KW - Bioisostere

KW - Bisphosphonate

KW - Geranylgeranyl diphosphate synthase

KW - Inhibition

KW - Isoprenoid biosynthesis

KW - Myeloma

KW - Triazole

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Amides as bioisosteres of triazole-based geranylgeranyl diphosphate synthase inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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