title: Synthesis, stereochemistry and SAR of a series of minodronate analogues as RGGT inhibitors.
abstract: Phosphonocarboxylate (PC) analogues of bisphosphonates are of interest due to their selective inhibition of a key enzyme in the mevalonate pathway, Rab geranylgeranyl transferase (RGGT). The dextrarotatory enantiomer of 2-hydroxy-3-(imidazo[1,2-a]pyridin-3-yl)-2-phosphonopropanoic acid (3-IPEHPC, 1) is the most potent PC-type RGGT inhibitor thus far identified. The absolute configuration of (+)-1 in the active site complex has remained unknown due to difficulties in obtaining RGGT inhibitor complex crystals suitable for X-ray diffraction analysis. However, we have now succeeded in crystallizing (-)-1 and here report its absolute configuration (AC) obtained by X-ray crystallography, thus also defining the AC of (+)-1. An Autodock Vina 1.1 computer modeling study of (+)-1 in the active site of modified RGGT binding GGPP (3DSV) identifies stereochemistry-dependent interactions that could account for the potency of (+)-1 and supports the hypothesis that this type of inhibitor binds at the TAG tunnel, inhibiting the second geranylgeranylation step. We also report a convenient (31)P NMR method to determine enantiomeric excess of 1 and its pyridyl analogue 2, using α- and β-cyclodextrins as chiral solvating agents, and describe the synthesis of a small series of 1 α-X (X = H, F, Cl, Br; 7a-d) analogues to assess the contribution of the α-OH group to activity at enzyme and cellular levels. The IC(50) of 1 was 5-10× lower than 7a-d, and the LED for inhibition of Rab11 prenylation in vitro was 2-8× lower than for 7a-d. However, in a viability reduction assay with J774 cells, 1 and 7b had similar IC(50) values, ~10× lower than those of 7a and 7c-d.
authors: Department of Chemistry, University of Southern California, Los Angeles, CA 90089-0744, USA.
authors: Katarzyna M
authors: KM
authors: Błażewska
authors: Feng
authors: F
authors: Ni
authors: Ralf
authors: R
authors: Haiges
authors: Boris A
authors: BA
authors: Kashemirov
authors: Fraser P
authors: FP
authors: Coxon
authors: Charlotte A
authors: CA
authors: Stewart
authors: Rudi
authors: R
authors: Baron
authors: Michael J
authors: MJ
authors: Rogers
authors: Miguel C
authors: MC
authors: Seabra
authors: Frank H
authors: FH
authors: Ebetino
authors: Charles E
authors: CE
authors: McKenna
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D004164:Diphosphonates / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D011485:Protein Binding; D013237:Stereoisomerism
chemical_list: D004164:Diphosphonates; D004791:Enzyme Inhibitors; D007093:Imidazoles; C087958:YM 529; D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase