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Markku Ahlgrén - One of the best experts on this subject based on the ideXlab platform.
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Alkaline and alkaline earth metal complexes of dianhydride derivatives of clodronate and their hydrolysis products
Dalton transactions (Cambridge England : 2003), 2010Co-Authors: Susan Kunnas-hiltunen, Jouko Vepsäläinen, Matti Haukka, Markku AhlgrénAbstract:Alkaline and alkaline earth metal complexes of P,P′-diacetyl- (L12−); new P,P′-dipropanoyl- (L22−) and P,P′-dibenzoyl(dichloromethylene)bisphosphonates (L32−) and their hydrolysis products were prepared and characterized using the single-crystal X-ray diffraction technique and spectroscopy, with the intention of studying the hydrolysis and coordinating properties of these potential prodrugs of clodronate. Na2L1 and Na2L2 formed the first crystalline hydrolysis product of these dianhydrides, 3D polymeric trisodium clodronate, [Na3{Cl2C(PO3)2}(H2O)4]n (1). The other metal complexes prepared comprised the polymeric Ba2+ complex of L12− ligand [Ba{Cl2C(PO2O(C(O)Me))2}(H2O)3]n (2); the new Sr2+ complex of Clodronic Acid [{Sr2(Cl2C(PO3)2)(H2O)4}·H2O]n (3), and the K+ complex of the L32− ligand [{K2Cl2C(PO2O(C(O)C6H5))2}O]n (4). In addition, these L12−–L32− ligands have formed the same, previously published [NaMgCl2CP2O6H)(H2O)5]n (5) and [{Ca2(Cl2C(PO3)2)(H2O)6}·4.5H2O]n (6) by using the hydrolysis method in a systematic way. This study revealed that the Na2L1 and Na2L2 hydrolyze quite fast to structure 1 or form hydrolyzed metal complexes of Clodronic Acid, and hence the absorption in the body may not be increased by the use of Na2L1-Na2L2 as prodrugs. Na2L3, in turn, has a longer hydrolysis time and generally forms crystalline polymeric metal complexes without undergoing hydrolyzation. In addition, the masking of the two phosphonic Acid groups by esterification to form Clodronic dianhydrides does not prevent the formation of 2D polymeric metal complexes, which methylenebisphosphonates form as drugs on the hydroxyapatite surface of bone. Clodronate, however, is able to extend the dimensionality to 3D by coordination or hydrogen bonding.
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syntheses x ray diffraction study and characterisations of ni and zn complexes of Clodronic Acid and its dibenzoyl derivative
European Journal of Inorganic Chemistry, 2009Co-Authors: Susan Kunnashiltunen, Jouko Vepsäläinen, Matti Haukka, Markku AhlgrénAbstract:Four new nickel and zinc bis(phosphonates) were prepared, and their crystal structures were determined by single-crystal X-ray diffractometry: [[Na 2 Ni 3 (Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 )-(H 2 O) 20 }{Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 }] n (1), [[Na 2 Zn 3 (Cl 2 C(PO 2 -O(C(O)C 6 H 5 )) 2 )(H 2 O) 20 }{Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 }] n (2), [Ni 2 -[Cl 2 C(PO 3 ) 2 }(H 2 O) 7 ]·4H 2 O (3) and [Zn 2 {Cl 2 C(PO 3 ) 2 }(H 2 O) 7 ]· 6H 2 0 (4). In addition, the spectroscopic and thermal properties of the compounds 1-4 were studied by infrared spectroscopy and thermogravimetric analysis. The coordination polymers 1 and 2 form, through intermolecular hydrogen bonds, 2D layer-like structures, whereas the aqua ligands and lattice water molecules of the monomeric compounds 3 and 4 form hydrogen bonds in three dimensions giving rise to a 3D network. In the isomorphous structures 1 and 2 the octahedral Na and Ni/Zn atoms form μ-H 2 O-bridged stepped metal chains where the Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 2- ligands (L1) are monodentately coordinated to the Na and Ni/Zn atoms, and the lattice L1 ligands are located in a trans position with respect to the chain. The isostructural Ni and Zn complexes of Clodronic Acid, 3 and 4, are formed by a hydrolysis method from the L1 ligand. There, the clodronate ligand acts as a bridging and chelating ligand with the octahedral Ni and Zn atoms. The bulky and hydrophopic benzoyl groups of the L1 ligand in structures 1 and 2 lead to dense packing modes. The Clodronic Acid ligand of structures 3 and 4, in turn, has a higher coordination flexibility and forms voids, where the water clusters are trapped by hydrogen bonds.
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Syntheses, X‐ray Diffraction Study and Characterisations of Ni and Zn Complexes of Clodronic Acid and Its Dibenzoyl Derivative
European Journal of Inorganic Chemistry, 2009Co-Authors: Susan Kunnas-hiltunen, Jouko Vepsäläinen, Matti Haukka, Markku AhlgrénAbstract:Four new nickel and zinc bis(phosphonates) were prepared, and their crystal structures were determined by single-crystal X-ray diffractometry: [[Na 2 Ni 3 (Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 )-(H 2 O) 20 }{Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 }] n (1), [[Na 2 Zn 3 (Cl 2 C(PO 2 -O(C(O)C 6 H 5 )) 2 )(H 2 O) 20 }{Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 }] n (2), [Ni 2 -[Cl 2 C(PO 3 ) 2 }(H 2 O) 7 ]·4H 2 O (3) and [Zn 2 {Cl 2 C(PO 3 ) 2 }(H 2 O) 7 ]· 6H 2 0 (4). In addition, the spectroscopic and thermal properties of the compounds 1-4 were studied by infrared spectroscopy and thermogravimetric analysis. The coordination polymers 1 and 2 form, through intermolecular hydrogen bonds, 2D layer-like structures, whereas the aqua ligands and lattice water molecules of the monomeric compounds 3 and 4 form hydrogen bonds in three dimensions giving rise to a 3D network. In the isomorphous structures 1 and 2 the octahedral Na and Ni/Zn atoms form μ-H 2 O-bridged stepped metal chains where the Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 2- ligands (L1) are monodentately coordinated to the Na and Ni/Zn atoms, and the lattice L1 ligands are located in a trans position with respect to the chain. The isostructural Ni and Zn complexes of Clodronic Acid, 3 and 4, are formed by a hydrolysis method from the L1 ligand. There, the clodronate ligand acts as a bridging and chelating ligand with the octahedral Ni and Zn atoms. The bulky and hydrophopic benzoyl groups of the L1 ligand in structures 1 and 2 lead to dense packing modes. The Clodronic Acid ligand of structures 3 and 4, in turn, has a higher coordination flexibility and forms voids, where the water clusters are trapped by hydrogen bonds.
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X-ray diffraction study of bisphosphonate metal complexes: Mg, Sr and Ba complexes of (dichloromethylene)bisphosphonic Acid P,P′-dibenzoyl anhydride
Polyhedron, 2009Co-Authors: Susan Kunnas-hiltunen, Jouko Vepsäläinen, Mervi Matilainen, Markku AhlgrénAbstract:The first alkaline earth metal complexes of a dibenzoyl derivative of Clodronic Acid were prepared and characterised by X-ray crystallography, elemental analysis and infrared spectroscopy. The complexes were [Mg{[Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 ](H 2 O) 5 } · H 2 O] ( 1 ), [Sr 2 {[Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 ] 2 (H 2 O) 9 } · H 2 O] n ( 2 ) and [Ba{Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 }(H 2 O) 2 ] n ( 3 ). The monomeric units of 1 and the polymeric chains of 2 and 3 form 2D layer-like structures through intermolecular hydrogen bonds. The Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 2− ligand acts as a bridging and chelating ligand, forming six- and eight-membered chelate rings with metal atoms. In addition, the previously determined polymeric calcium complex of clodronate, [Ca 2 {Cl 2 C(PO 3 ) 2 }(H 2 O) 6 · 4.5H 2 O] n (4) , was synthesised by hydrolysis method from the dibenzoyl derivative of Clodronic Acid.
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x ray diffraction study of polymeric mg complexes of Clodronic Acid
Solid State Sciences, 2006Co-Authors: Mervi Kontturi, Jouko Vepsäläinen, Susan Kunnashiltunen, Markku AhlgrénAbstract:Abstract Two Mg complexes of (dichloromethylene)bisphosphonic Acid disodium salt, [{Mg(H 2 O) 6 }{Mg(Cl 2 CP 2 O 6 )(H 2 O)}⋅7H 2 O] n ( 1 ) and [NaMg(Cl 2 CP 2 O 6 H)(H 2 O) 5 ] n ( 2 ), were prepared and characterised by X-ray crystallography. The two compounds consist of similar one-dimensional magnesium clodronate chains; in 1 , [Mg(H 2 O) 6 ] 2+ cations are located between the chains; and in 2 , coordinated Na + cations hold the chains together in a three-dimensional network. The packing of 1 resembles layers, with the chlorine atoms of clodronate pointing toward the interlayer section, which is filled with lattice water molecules; and a wide hydrogen network is formed in all three dimensions. The framework of 2 contains channels, surrounded by the Cl and O atoms of clodronate, and aqua ligands; the channels are occupied by water molecules.
Jouko Vepsäläinen - One of the best experts on this subject based on the ideXlab platform.
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Alkaline and alkaline earth metal complexes of dianhydride derivatives of clodronate and their hydrolysis products
Dalton transactions (Cambridge England : 2003), 2010Co-Authors: Susan Kunnas-hiltunen, Jouko Vepsäläinen, Matti Haukka, Markku AhlgrénAbstract:Alkaline and alkaline earth metal complexes of P,P′-diacetyl- (L12−); new P,P′-dipropanoyl- (L22−) and P,P′-dibenzoyl(dichloromethylene)bisphosphonates (L32−) and their hydrolysis products were prepared and characterized using the single-crystal X-ray diffraction technique and spectroscopy, with the intention of studying the hydrolysis and coordinating properties of these potential prodrugs of clodronate. Na2L1 and Na2L2 formed the first crystalline hydrolysis product of these dianhydrides, 3D polymeric trisodium clodronate, [Na3{Cl2C(PO3)2}(H2O)4]n (1). The other metal complexes prepared comprised the polymeric Ba2+ complex of L12− ligand [Ba{Cl2C(PO2O(C(O)Me))2}(H2O)3]n (2); the new Sr2+ complex of Clodronic Acid [{Sr2(Cl2C(PO3)2)(H2O)4}·H2O]n (3), and the K+ complex of the L32− ligand [{K2Cl2C(PO2O(C(O)C6H5))2}O]n (4). In addition, these L12−–L32− ligands have formed the same, previously published [NaMgCl2CP2O6H)(H2O)5]n (5) and [{Ca2(Cl2C(PO3)2)(H2O)6}·4.5H2O]n (6) by using the hydrolysis method in a systematic way. This study revealed that the Na2L1 and Na2L2 hydrolyze quite fast to structure 1 or form hydrolyzed metal complexes of Clodronic Acid, and hence the absorption in the body may not be increased by the use of Na2L1-Na2L2 as prodrugs. Na2L3, in turn, has a longer hydrolysis time and generally forms crystalline polymeric metal complexes without undergoing hydrolyzation. In addition, the masking of the two phosphonic Acid groups by esterification to form Clodronic dianhydrides does not prevent the formation of 2D polymeric metal complexes, which methylenebisphosphonates form as drugs on the hydroxyapatite surface of bone. Clodronate, however, is able to extend the dimensionality to 3D by coordination or hydrogen bonding.
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syntheses x ray diffraction study and characterisations of ni and zn complexes of Clodronic Acid and its dibenzoyl derivative
European Journal of Inorganic Chemistry, 2009Co-Authors: Susan Kunnashiltunen, Jouko Vepsäläinen, Matti Haukka, Markku AhlgrénAbstract:Four new nickel and zinc bis(phosphonates) were prepared, and their crystal structures were determined by single-crystal X-ray diffractometry: [[Na 2 Ni 3 (Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 )-(H 2 O) 20 }{Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 }] n (1), [[Na 2 Zn 3 (Cl 2 C(PO 2 -O(C(O)C 6 H 5 )) 2 )(H 2 O) 20 }{Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 }] n (2), [Ni 2 -[Cl 2 C(PO 3 ) 2 }(H 2 O) 7 ]·4H 2 O (3) and [Zn 2 {Cl 2 C(PO 3 ) 2 }(H 2 O) 7 ]· 6H 2 0 (4). In addition, the spectroscopic and thermal properties of the compounds 1-4 were studied by infrared spectroscopy and thermogravimetric analysis. The coordination polymers 1 and 2 form, through intermolecular hydrogen bonds, 2D layer-like structures, whereas the aqua ligands and lattice water molecules of the monomeric compounds 3 and 4 form hydrogen bonds in three dimensions giving rise to a 3D network. In the isomorphous structures 1 and 2 the octahedral Na and Ni/Zn atoms form μ-H 2 O-bridged stepped metal chains where the Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 2- ligands (L1) are monodentately coordinated to the Na and Ni/Zn atoms, and the lattice L1 ligands are located in a trans position with respect to the chain. The isostructural Ni and Zn complexes of Clodronic Acid, 3 and 4, are formed by a hydrolysis method from the L1 ligand. There, the clodronate ligand acts as a bridging and chelating ligand with the octahedral Ni and Zn atoms. The bulky and hydrophopic benzoyl groups of the L1 ligand in structures 1 and 2 lead to dense packing modes. The Clodronic Acid ligand of structures 3 and 4, in turn, has a higher coordination flexibility and forms voids, where the water clusters are trapped by hydrogen bonds.
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Syntheses, X‐ray Diffraction Study and Characterisations of Ni and Zn Complexes of Clodronic Acid and Its Dibenzoyl Derivative
European Journal of Inorganic Chemistry, 2009Co-Authors: Susan Kunnas-hiltunen, Jouko Vepsäläinen, Matti Haukka, Markku AhlgrénAbstract:Four new nickel and zinc bis(phosphonates) were prepared, and their crystal structures were determined by single-crystal X-ray diffractometry: [[Na 2 Ni 3 (Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 )-(H 2 O) 20 }{Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 }] n (1), [[Na 2 Zn 3 (Cl 2 C(PO 2 -O(C(O)C 6 H 5 )) 2 )(H 2 O) 20 }{Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 }] n (2), [Ni 2 -[Cl 2 C(PO 3 ) 2 }(H 2 O) 7 ]·4H 2 O (3) and [Zn 2 {Cl 2 C(PO 3 ) 2 }(H 2 O) 7 ]· 6H 2 0 (4). In addition, the spectroscopic and thermal properties of the compounds 1-4 were studied by infrared spectroscopy and thermogravimetric analysis. The coordination polymers 1 and 2 form, through intermolecular hydrogen bonds, 2D layer-like structures, whereas the aqua ligands and lattice water molecules of the monomeric compounds 3 and 4 form hydrogen bonds in three dimensions giving rise to a 3D network. In the isomorphous structures 1 and 2 the octahedral Na and Ni/Zn atoms form μ-H 2 O-bridged stepped metal chains where the Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 2- ligands (L1) are monodentately coordinated to the Na and Ni/Zn atoms, and the lattice L1 ligands are located in a trans position with respect to the chain. The isostructural Ni and Zn complexes of Clodronic Acid, 3 and 4, are formed by a hydrolysis method from the L1 ligand. There, the clodronate ligand acts as a bridging and chelating ligand with the octahedral Ni and Zn atoms. The bulky and hydrophopic benzoyl groups of the L1 ligand in structures 1 and 2 lead to dense packing modes. The Clodronic Acid ligand of structures 3 and 4, in turn, has a higher coordination flexibility and forms voids, where the water clusters are trapped by hydrogen bonds.
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X-ray diffraction study of bisphosphonate metal complexes: Mg, Sr and Ba complexes of (dichloromethylene)bisphosphonic Acid P,P′-dibenzoyl anhydride
Polyhedron, 2009Co-Authors: Susan Kunnas-hiltunen, Jouko Vepsäläinen, Mervi Matilainen, Markku AhlgrénAbstract:The first alkaline earth metal complexes of a dibenzoyl derivative of Clodronic Acid were prepared and characterised by X-ray crystallography, elemental analysis and infrared spectroscopy. The complexes were [Mg{[Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 ](H 2 O) 5 } · H 2 O] ( 1 ), [Sr 2 {[Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 ] 2 (H 2 O) 9 } · H 2 O] n ( 2 ) and [Ba{Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 }(H 2 O) 2 ] n ( 3 ). The monomeric units of 1 and the polymeric chains of 2 and 3 form 2D layer-like structures through intermolecular hydrogen bonds. The Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 2− ligand acts as a bridging and chelating ligand, forming six- and eight-membered chelate rings with metal atoms. In addition, the previously determined polymeric calcium complex of clodronate, [Ca 2 {Cl 2 C(PO 3 ) 2 }(H 2 O) 6 · 4.5H 2 O] n (4) , was synthesised by hydrolysis method from the dibenzoyl derivative of Clodronic Acid.
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x ray diffraction study of polymeric mg complexes of Clodronic Acid
Solid State Sciences, 2006Co-Authors: Mervi Kontturi, Jouko Vepsäläinen, Susan Kunnashiltunen, Markku AhlgrénAbstract:Abstract Two Mg complexes of (dichloromethylene)bisphosphonic Acid disodium salt, [{Mg(H 2 O) 6 }{Mg(Cl 2 CP 2 O 6 )(H 2 O)}⋅7H 2 O] n ( 1 ) and [NaMg(Cl 2 CP 2 O 6 H)(H 2 O) 5 ] n ( 2 ), were prepared and characterised by X-ray crystallography. The two compounds consist of similar one-dimensional magnesium clodronate chains; in 1 , [Mg(H 2 O) 6 ] 2+ cations are located between the chains; and in 2 , coordinated Na + cations hold the chains together in a three-dimensional network. The packing of 1 resembles layers, with the chlorine atoms of clodronate pointing toward the interlayer section, which is filled with lattice water molecules; and a wide hydrogen network is formed in all three dimensions. The framework of 2 contains channels, surrounded by the Cl and O atoms of clodronate, and aqua ligands; the channels are occupied by water molecules.
Tomi Järvinen - One of the best experts on this subject based on the ideXlab platform.
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Bisphosphonate prodrugs: unusual dimerisation of Clodronic Acid trimethyl ester to a cyclic bis(bisphosphonate)
Chemical Communications, 2000Co-Authors: Marko Ahlmark, Riku Niemi, Hannu Taipale, Tomi Järvinen, Markku Ahlgrén, Jouko VepsäläinenAbstract:Cl2C[P(O)(OMe)2P(O)(OMe)(O− Z+)] selectively reacts with acetyl chloride to provide a new enzymatically stable heterocyclic bis(bisphosphonate); the structure is confirmed by X-ray crystallography.
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Bisphosphonate prodrugs: synthesis and in vitro evaluation of novel acyloxyalkyl esters of Clodronic Acid.
Journal of medicinal chemistry, 1999Co-Authors: Riku Niemi, Jouko Vepsäläinen, Hannu Taipale, Tomi JärvinenAbstract:Novel tetra-, tri-, and P,P'-dipivaloyloxymethyl esters of Clodronic Acid were synthesized, and their properties as possible prodrugs of clodronate were evaluated in vitro. All pivaloyloxymethyl esters were significantly more lipophilic (log P(app) ranged from -2.1 to 7. 4) than clodronate (log P(app) < or = -5.4), which suggests that it may be possible to change the intestinal absorption mechanism of clodronate from a paracellular to a transcellular pathway by a prodrug approach. Pivaloyloxymethyl esters degraded rapidly in 10% rabbit liver homogenate, and half-lives of tri- and P,P'-diesters were 1.1 and 14 min, respectively. The intermediate degradation products were further degraded, and Clodronic Acid was released in quantitative amounts. In human serum, the stability of pivaloyloxymethyl esters was comparable to their stability in phosphate buffer (pH 7.4), which suggests that their degradation in human serum is mostly due to the chemical hydrolysis. Benzoyloxypropyl esters of Clodronic Acid were also synthesized, but they did not release Clodronic Acid due to the enzymatic and chemical stability of the formed 3-hydroxypropyl phosphonate esters and are, therefore, not prodrugs.
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Bisphosphonate prodrugs: synthesis and in vitro evaluation of novel Clodronic Acid dianhydrides as bioreversible prodrugs of clodronate.
Journal of medicinal chemistry, 1999Co-Authors: Marko Ahlmark, Riku Niemi, Jouko Vepsäläinen, Hannu Taipale, Tomi JärvinenAbstract:P,P‘-Diacetyl, P,P‘-dibutyroyl, P,P‘-dipivaloyl, and P,P‘-dibenzoyl (dichloromethylene)bisphosphonic Acid dianhydride disodium salts (2a−d) were synthesized and evaluated as novel bioreversible prodrugs of clodronate. The anhydrides were prepared by reacting anhydrous tetrasodium clodronate with a large excess of the corresponding Acid anhydride. The dianhydrides 2a−d alone were more lipophilic than the parent clodronate, as determined by drug partitioning between 1-octanol and phosphate buffer at pH 7.4. They also were stable toward chemical hydrolysis in aqueous solutions (pH 7.4 and 2.0). The half-lives for chemical degradation in a buffer solution at 37 °C varied from 0.7 to 286 h and from 15 to 790 h at pH 2.0 and 7.4, respectively. The dianhydrides 2a,b,d underwent complete enzymatic hydrolysis to clodronate in 80% serum at 37 °C after 1 min, although 2c had a half-life of 3.3 h. The aqueous solubility of clodronate decreased considerably in the presence of Ca2+ ions. This is most probably due to fo...
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bisphosphonate prodrugs synthesis and in vitro evaluation of novel partial amides of Clodronic Acid
International Journal of Pharmaceutics, 1998Co-Authors: Riku Niemi, Jouko Vepsäläinen, Hannu Taipale, Heli Pennanen, Tomi JärvinenAbstract:Abstract Novel partial amides of Clodronic Acid were synthesized and evaluated in vitro for their properties as bioreversible prodrugs of clodronate. The hydrolysis studies indicated that these derivatives release the parent drug via chemical hydrolysis. Monoamides were hydrolysed rapidly ( t 1/2 =16–19 min at pH 7.4) to Clodronic Acid, which suggests that they are useful intermediates in the design of enzymatically labile double prodrugs of clodronate.
Susan Kunnas-hiltunen - One of the best experts on this subject based on the ideXlab platform.
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Alkaline and alkaline earth metal complexes of dianhydride derivatives of clodronate and their hydrolysis products
Dalton transactions (Cambridge England : 2003), 2010Co-Authors: Susan Kunnas-hiltunen, Jouko Vepsäläinen, Matti Haukka, Markku AhlgrénAbstract:Alkaline and alkaline earth metal complexes of P,P′-diacetyl- (L12−); new P,P′-dipropanoyl- (L22−) and P,P′-dibenzoyl(dichloromethylene)bisphosphonates (L32−) and their hydrolysis products were prepared and characterized using the single-crystal X-ray diffraction technique and spectroscopy, with the intention of studying the hydrolysis and coordinating properties of these potential prodrugs of clodronate. Na2L1 and Na2L2 formed the first crystalline hydrolysis product of these dianhydrides, 3D polymeric trisodium clodronate, [Na3{Cl2C(PO3)2}(H2O)4]n (1). The other metal complexes prepared comprised the polymeric Ba2+ complex of L12− ligand [Ba{Cl2C(PO2O(C(O)Me))2}(H2O)3]n (2); the new Sr2+ complex of Clodronic Acid [{Sr2(Cl2C(PO3)2)(H2O)4}·H2O]n (3), and the K+ complex of the L32− ligand [{K2Cl2C(PO2O(C(O)C6H5))2}O]n (4). In addition, these L12−–L32− ligands have formed the same, previously published [NaMgCl2CP2O6H)(H2O)5]n (5) and [{Ca2(Cl2C(PO3)2)(H2O)6}·4.5H2O]n (6) by using the hydrolysis method in a systematic way. This study revealed that the Na2L1 and Na2L2 hydrolyze quite fast to structure 1 or form hydrolyzed metal complexes of Clodronic Acid, and hence the absorption in the body may not be increased by the use of Na2L1-Na2L2 as prodrugs. Na2L3, in turn, has a longer hydrolysis time and generally forms crystalline polymeric metal complexes without undergoing hydrolyzation. In addition, the masking of the two phosphonic Acid groups by esterification to form Clodronic dianhydrides does not prevent the formation of 2D polymeric metal complexes, which methylenebisphosphonates form as drugs on the hydroxyapatite surface of bone. Clodronate, however, is able to extend the dimensionality to 3D by coordination or hydrogen bonding.
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Syntheses, X‐ray Diffraction Study and Characterisations of Ni and Zn Complexes of Clodronic Acid and Its Dibenzoyl Derivative
European Journal of Inorganic Chemistry, 2009Co-Authors: Susan Kunnas-hiltunen, Jouko Vepsäläinen, Matti Haukka, Markku AhlgrénAbstract:Four new nickel and zinc bis(phosphonates) were prepared, and their crystal structures were determined by single-crystal X-ray diffractometry: [[Na 2 Ni 3 (Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 )-(H 2 O) 20 }{Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 }] n (1), [[Na 2 Zn 3 (Cl 2 C(PO 2 -O(C(O)C 6 H 5 )) 2 )(H 2 O) 20 }{Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 }] n (2), [Ni 2 -[Cl 2 C(PO 3 ) 2 }(H 2 O) 7 ]·4H 2 O (3) and [Zn 2 {Cl 2 C(PO 3 ) 2 }(H 2 O) 7 ]· 6H 2 0 (4). In addition, the spectroscopic and thermal properties of the compounds 1-4 were studied by infrared spectroscopy and thermogravimetric analysis. The coordination polymers 1 and 2 form, through intermolecular hydrogen bonds, 2D layer-like structures, whereas the aqua ligands and lattice water molecules of the monomeric compounds 3 and 4 form hydrogen bonds in three dimensions giving rise to a 3D network. In the isomorphous structures 1 and 2 the octahedral Na and Ni/Zn atoms form μ-H 2 O-bridged stepped metal chains where the Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 2- ligands (L1) are monodentately coordinated to the Na and Ni/Zn atoms, and the lattice L1 ligands are located in a trans position with respect to the chain. The isostructural Ni and Zn complexes of Clodronic Acid, 3 and 4, are formed by a hydrolysis method from the L1 ligand. There, the clodronate ligand acts as a bridging and chelating ligand with the octahedral Ni and Zn atoms. The bulky and hydrophopic benzoyl groups of the L1 ligand in structures 1 and 2 lead to dense packing modes. The Clodronic Acid ligand of structures 3 and 4, in turn, has a higher coordination flexibility and forms voids, where the water clusters are trapped by hydrogen bonds.
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X-ray diffraction study of bisphosphonate metal complexes: Mg, Sr and Ba complexes of (dichloromethylene)bisphosphonic Acid P,P′-dibenzoyl anhydride
Polyhedron, 2009Co-Authors: Susan Kunnas-hiltunen, Jouko Vepsäläinen, Mervi Matilainen, Markku AhlgrénAbstract:The first alkaline earth metal complexes of a dibenzoyl derivative of Clodronic Acid were prepared and characterised by X-ray crystallography, elemental analysis and infrared spectroscopy. The complexes were [Mg{[Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 ](H 2 O) 5 } · H 2 O] ( 1 ), [Sr 2 {[Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 ] 2 (H 2 O) 9 } · H 2 O] n ( 2 ) and [Ba{Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 }(H 2 O) 2 ] n ( 3 ). The monomeric units of 1 and the polymeric chains of 2 and 3 form 2D layer-like structures through intermolecular hydrogen bonds. The Cl 2 C(PO 2 O(C(O)C 6 H 5 )) 2 2− ligand acts as a bridging and chelating ligand, forming six- and eight-membered chelate rings with metal atoms. In addition, the previously determined polymeric calcium complex of clodronate, [Ca 2 {Cl 2 C(PO 3 ) 2 }(H 2 O) 6 · 4.5H 2 O] n (4) , was synthesised by hydrolysis method from the dibenzoyl derivative of Clodronic Acid.
Riku Niemi - One of the best experts on this subject based on the ideXlab platform.
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Bisphosphonate prodrugs: unusual dimerisation of Clodronic Acid trimethyl ester to a cyclic bis(bisphosphonate)
Chemical Communications, 2000Co-Authors: Marko Ahlmark, Riku Niemi, Hannu Taipale, Tomi Järvinen, Markku Ahlgrén, Jouko VepsäläinenAbstract:Cl2C[P(O)(OMe)2P(O)(OMe)(O− Z+)] selectively reacts with acetyl chloride to provide a new enzymatically stable heterocyclic bis(bisphosphonate); the structure is confirmed by X-ray crystallography.
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Bisphosphonate prodrugs: synthesis and in vitro evaluation of novel acyloxyalkyl esters of Clodronic Acid.
Journal of medicinal chemistry, 1999Co-Authors: Riku Niemi, Jouko Vepsäläinen, Hannu Taipale, Tomi JärvinenAbstract:Novel tetra-, tri-, and P,P'-dipivaloyloxymethyl esters of Clodronic Acid were synthesized, and their properties as possible prodrugs of clodronate were evaluated in vitro. All pivaloyloxymethyl esters were significantly more lipophilic (log P(app) ranged from -2.1 to 7. 4) than clodronate (log P(app) < or = -5.4), which suggests that it may be possible to change the intestinal absorption mechanism of clodronate from a paracellular to a transcellular pathway by a prodrug approach. Pivaloyloxymethyl esters degraded rapidly in 10% rabbit liver homogenate, and half-lives of tri- and P,P'-diesters were 1.1 and 14 min, respectively. The intermediate degradation products were further degraded, and Clodronic Acid was released in quantitative amounts. In human serum, the stability of pivaloyloxymethyl esters was comparable to their stability in phosphate buffer (pH 7.4), which suggests that their degradation in human serum is mostly due to the chemical hydrolysis. Benzoyloxypropyl esters of Clodronic Acid were also synthesized, but they did not release Clodronic Acid due to the enzymatic and chemical stability of the formed 3-hydroxypropyl phosphonate esters and are, therefore, not prodrugs.
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Bisphosphonate prodrugs: synthesis and in vitro evaluation of novel Clodronic Acid dianhydrides as bioreversible prodrugs of clodronate.
Journal of medicinal chemistry, 1999Co-Authors: Marko Ahlmark, Riku Niemi, Jouko Vepsäläinen, Hannu Taipale, Tomi JärvinenAbstract:P,P‘-Diacetyl, P,P‘-dibutyroyl, P,P‘-dipivaloyl, and P,P‘-dibenzoyl (dichloromethylene)bisphosphonic Acid dianhydride disodium salts (2a−d) were synthesized and evaluated as novel bioreversible prodrugs of clodronate. The anhydrides were prepared by reacting anhydrous tetrasodium clodronate with a large excess of the corresponding Acid anhydride. The dianhydrides 2a−d alone were more lipophilic than the parent clodronate, as determined by drug partitioning between 1-octanol and phosphate buffer at pH 7.4. They also were stable toward chemical hydrolysis in aqueous solutions (pH 7.4 and 2.0). The half-lives for chemical degradation in a buffer solution at 37 °C varied from 0.7 to 286 h and from 15 to 790 h at pH 2.0 and 7.4, respectively. The dianhydrides 2a,b,d underwent complete enzymatic hydrolysis to clodronate in 80% serum at 37 °C after 1 min, although 2c had a half-life of 3.3 h. The aqueous solubility of clodronate decreased considerably in the presence of Ca2+ ions. This is most probably due to fo...
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bisphosphonate prodrugs synthesis and in vitro evaluation of novel partial amides of Clodronic Acid
International Journal of Pharmaceutics, 1998Co-Authors: Riku Niemi, Jouko Vepsäläinen, Hannu Taipale, Heli Pennanen, Tomi JärvinenAbstract:Abstract Novel partial amides of Clodronic Acid were synthesized and evaluated in vitro for their properties as bioreversible prodrugs of clodronate. The hydrolysis studies indicated that these derivatives release the parent drug via chemical hydrolysis. Monoamides were hydrolysed rapidly ( t 1/2 =16–19 min at pH 7.4) to Clodronic Acid, which suggests that they are useful intermediates in the design of enzymatically labile double prodrugs of clodronate.