Pyridinium-1-yl bisphosphonates are potent inhibitors of farnesyl diphosphate synthase and bone resorption.
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.
Sanders
John M
JM
Department of Chemistry, 600 South Mathews Avenue, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Song
Yongcheng
Y
Chan
Julian M W
JM
Zhang
Yonghui
Y
Jennings
Samuel
S
Kosztowski
Thomas
T
Odeh
Sarah
S
Flessner
Ryan
R
Schwerdtfeger
Christine
C
Kotsikorou
Evangelia
E
Meints
Gary A
GA
Gómez
Aurora Ortiz
AO
González-Pacanowska
Dolores
D
Raker
Amy M
AM
Wang
Hong
H
van Beek
Ermond R
ER
Papapoulos
Socrates E
SE
Morita
Craig T
CT
Oldfield
Eric
E
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
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