Abstract
Alpha-halogenated analogues of the anti-resorptive bisphosphonate risedronate (5, Ris) and its phosphonocarboxylate cognate (7, 3-PEHPC) were synthesized and compared with 5, 7, and the corresponding desoxy analogues in bone mineral affinity and mevalonate pathway inhibition assays. The Ris (5e-h) and 3-PEHPC (7e-h) analogues had decreased bone mineral affinity, confirming that the alpha-OH group in 5 and 7 enhances bone affinity. The 5 alpha-halo-analogues potently inhibited farnesyl pyrophosphate synthase (FPPS) with IC50 values from 16 (alpha-F) to 340 (alpha-Br) nM (5, 6 nM). In contrast, 7 alpha-halo-analogues were ineffective versus FPPS (IC50 > 600 microM), but inhibited Rab geranylgeranyl transferase (RGGT) (IC50 = 16-35 microM) similarly to 7 itself (IC50 = 24 microM). The alpha-F analogue 7e was 1-2 times as active as 7 in J774 cell viability and Rab11 prenylation inhibition assays.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors
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Animals
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Bone Density Conservation Agents / chemical synthesis*
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Bone Density Conservation Agents / chemistry
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Bone Density Conservation Agents / pharmacology
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Cell Line
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Cell Proliferation
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Cell Survival / drug effects
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Chromatography, Liquid
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Diphosphonates / chemical synthesis*
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Diphosphonates / chemistry
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Diphosphonates / pharmacology
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Durapatite / chemistry
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Etidronic Acid / analogs & derivatives*
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Etidronic Acid / chemical synthesis
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Etidronic Acid / chemistry
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Etidronic Acid / pharmacology
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Geranyltranstransferase / antagonists & inhibitors
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Mice
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Organophosphonates / chemical synthesis*
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Organophosphonates / chemistry
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Organophosphonates / pharmacology
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Propionates / chemical synthesis*
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Propionates / chemistry
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Propionates / pharmacology
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Protein Prenylation / drug effects
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacology
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Risedronic Acid
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Structure-Activity Relationship
Substances
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1-fluoro-2-(3-pyridinyl)ethylidene-1,1-bisphosphonic acid
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2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid
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2-fluoro-3-(3-pyridinyl)-2-phosphonopropionic acid
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Bone Density Conservation Agents
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Diphosphonates
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Organophosphonates
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Propionates
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Pyridines
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Durapatite
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Alkyl and Aryl Transferases
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Rab geranylgeranyltransferase
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Geranyltranstransferase
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Risedronic Acid
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Etidronic Acid