title: Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption.
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.
authors.affiliation: Department of Chemistry, 600 South Mathews Avenue, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Sanders
authors.forename: Yongcheng
authors.initials: Y
authors.lastname: Song
authors.forename: Julian M W
authors.initials: JM
authors.lastname: Chan
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Samuel
authors.initials: S
authors.lastname: Jennings
authors.forename: Thomas
authors.initials: T
authors.lastname: Kosztowski
authors.forename: Sarah
authors.initials: S
authors.lastname: Odeh
authors.forename: Ryan
authors.initials: R
authors.lastname: Flessner
authors.forename: Christine
authors.initials: C
authors.lastname: Schwerdtfeger
authors.forename: Evangelia
authors.initials: E
authors.lastname: Kotsikorou
authors.forename: Gary A
authors.initials: GA
authors.lastname: Meints
authors.forename: Aurora Ortiz
authors.initials: AO
authors.lastname: Gómez
authors.forename: Dolores
authors.initials: D
authors.lastname: González-Pacanowska
authors.forename: Amy M
authors.initials: AM
authors.lastname: Raker
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Ermond R
authors.initials: ER
authors.lastname: van Beek
authors.forename: Socrates E
authors.initials: SE
authors.lastname: Papapoulos
authors.forename: Craig T
authors.initials: CT
authors.lastname: Morita
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D004023:Dictyostelium / Q000187:drug effects / Q000201:enzymology; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051228:Geranyltranstransferase; D006801:Humans; D066298:In Vitro Techniques; D018320:Leishmania major / Q000201:enzymology; D008682:Metatarsal Bones / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D011726:Pyridinium Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000819:agonists; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004164:Diphosphonates; D011726:Pyridinium Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014344:Trypanocidal Agents; D019883:Alkyl and Aryl Transferases; D051228:Geranyltranstransferase; D002118:Calcium