Synthesis and biological evaluation of alpha-halogenated bisphosphonate and phosphonocarboxylate analogues of risedronate.
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.
Marma
Mong S
MS
Department of Chemistry, University of Southern California, Los Angeles, CA 90089-0744, USA.
Xia
Zhidao
Z
Stewart
Charlotte
C
Coxon
Fraser
F
Dunford
James E
JE
Baron
Rudi
R
Kashemirov
Boris A
BA
Ebetino
Frank H
FH
Triffitt
James T
JT
Russell
R Graham G
RG
McKenna
Charles E
CE
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors; D000818:Animals; D050071:Bone Density Conservation Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D002853:Chromatography, Liquid; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017886:Durapatite / Q000737:chemistry; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051228:Geranyltranstransferase / Q000037:antagonists & inhibitors; D051379:Mice; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000068296:Risedronic Acid; D013329:Structure-Activity Relationship
C526809:1-fluoro-2-(3-pyridinyl)ethylidene-1,1-bisphosphonic acid; C410028:2-(3-pyridinyl)-1-hydroxyethylidene-1,1-phosphonocarboxylic acid; C526810:2-fluoro-3-(3-pyridinyl)-2-phosphonopropionic acid; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D063065:Organophosphonates; D011422:Propionates; D011725:Pyridines; D017886:Durapatite; D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase; D051228:Geranyltranstransferase; D000068296:Risedronic Acid; D012968:Etidronic Acid