Abstract
We report the design, synthesis and testing of a series of novel bisphosphonates, pyridinium-1-yl-hydroxy-bisphosphonates, based on the results of comparative molecular similarity indices analysis and pharmacophore modeling studies of farnesyl diphosphate synthase (FPPS) inhibition, human Vgamma2Vdelta2 T cell activation and bone resorption inhibition. The most potent molecules have high activity against an expressed FPPS from Leishmania major, in Dictyostelium discoideum growth inhibition, in gammadelta T cell activation and in an in vitro bone resorption assay. As such, they represent useful new leads for the discovery of new bone resorption, antiinfective and anticancer drugs.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Bone Resorption / drug therapy*
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Bone Resorption / metabolism
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Calcium / metabolism
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Dictyostelium / drug effects
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Dictyostelium / enzymology
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Diphosphonates / chemical synthesis*
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Diphosphonates / chemistry
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Diphosphonates / pharmacology
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Geranyltranstransferase
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Humans
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In Vitro Techniques
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Leishmania major / enzymology
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Metatarsal Bones / drug effects
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Metatarsal Bones / metabolism
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Mice
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Models, Molecular
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Pyridinium Compounds / chemical synthesis*
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Pyridinium Compounds / chemistry
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Pyridinium Compounds / pharmacology
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Quantitative Structure-Activity Relationship
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Receptors, Antigen, T-Cell, gamma-delta / agonists
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Trypanocidal Agents / chemical synthesis
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Trypanocidal Agents / chemistry
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Trypanocidal Agents / pharmacology
Substances
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Antineoplastic Agents
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Diphosphonates
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Pyridinium Compounds
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Receptors, Antigen, T-Cell, gamma-delta
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Trypanocidal Agents
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Alkyl and Aryl Transferases
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Geranyltranstransferase
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Calcium