ABSTRACT
The complex formed from crystallization of human farnesyl pyrophosphate synthase (hFPPS) from a solution of racemic [6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl(hydroxy)methylene]bis(phosphonic acid) (NE-10501, 8), a chiral analog of the anti-osteoporotic drug risedronate, contained the R enantiomer in the enzyme active site. This enantiospecificity was assessed by computer modeling of inhibitor-active site interactions using Autodock 3, which was also evaluated for predictive ability in calculations of the known configurations of risedronate, zoledronate, and minodronate complexed in the active site of hFPPS. In comparison with these structures, the 8 complex exhibited certain differences, including the presence of only one Mg(2+), which could contribute to its 100-fold higher IC(50). An improved synthesis of 8 is described, which decreases the number of steps from 12 to 8 and increases the overall yield by 17-fold.
Subject(s)
Bone Density Conservation Agents/pharmacology , Computer Simulation , Enzyme Inhibitors/pharmacology , Etidronic Acid/analogs & derivatives , Farnesyltranstransferase/antagonists & inhibitors , Organophosphonates/pharmacology , Pyridines/pharmacology , Algorithms , Binding Sites , Bone Density Conservation Agents/chemical synthesis , Carcinoma/drug therapy , Carcinoma/enzymology , Crystallography, X-Ray , Diphosphonates/chemistry , Diphosphonates/pharmacology , Enzyme Inhibitors/chemical synthesis , Etidronic Acid/chemistry , Etidronic Acid/pharmacology , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Inhibitory Concentration 50 , Magnesium/chemistry , Magnesium/metabolism , Models, Chemical , Organophosphonates/chemical synthesis , Pyridines/chemical synthesis , Risedronic Acid , Stereoisomerism , Structure-Activity Relationship , Zoledronic AcidABSTRACT
[reaction: see text] The room-temperature radical addition of sodium hypophosphite to terminal alkynes produces the previously unknown 1-alkyl-1,1-bis-H-phosphinates in moderate yield. The reaction is initiated by R3B and air and proceeds under mild conditions in an open container. The bissodium salts precipitate spontaneously from the reaction mixtures, thus providing a simple purification procedure and the opportunity for multigram synthesis. The 1,1-bis-H-phosphinate products are novel precursors of the biologically important 1,1-bisphosphonates.
Subject(s)
Alkynes/chemistry , Organophosphorus Compounds/chemical synthesis , Phosphinic Acids/chemistry , Catalysis , Molecular Structure , Organophosphorus Compounds/chemistryABSTRACT
[reaction: see text] A reusable polymer-supported hydrophosphinylation catalyst is described for the preparation of H-phosphinic acids. The polystyrene-based ligand is prepared in one step from commercially available compounds. The polymeric catalyst generally gives good yields for a variety of substrates and is water- and air-tolerant, although the scope of alkenes and alkynes which can be employed is somewhat narrower than with our original xantphos/Pd(2)dba(3) catalyst.
ABSTRACT
Various palladium catalysts promote the addition of hypophosphorous derivatives ROP(O)H(2) to alkenes and alkynes in good yields and under mild conditions. Particularly, Cl(2)Pd(PPh(3))(2)/2 MeLi, and Pd(2)dba(3)/xantphos allow for phosphorus-carbon bond formation instead of transfer hydrogenation. Commercial aqueous solutions of hypophosphorous acid can be employed successfully at ambient temperature. With styrene and terminal alkynes, the regioselectivity (linear versus branched products) can be controlled to some extent with the catalytic system employed. The methodology considerably extends upon previous routes for the preparation of H-phosphinic acids and other organophosphorus compounds.
