Synthesis of the water soluble ligands dmPTA and dmoPTA and the complex [RuClCp(HdmoPTA)(PPh(3))](OSO(2)CF(3)) (dmPTA = N,N'-Dimethyl-1,3,5-triaza-7-phosphaadamantane, dmoPTA = 3,7-Dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane, HdmoPTA = 3,7-H-3,7-Dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane)

The new water-soluble ligand dmPTA(OSO(2)CF(3))(2) (1) (dmPTA = N,N'-dimethyl-1,3,5-triaza-7-phosphaadamantane) has been synthesized by reaction of PTA with MeOSO(2)CF(3) in acetone (PTA = 1,3,5-triaza-7-phosphatricycle[3.3.1.1(3,7)]decane). The reaction of 1 with KOH gave rise to the new water-soluble ligand dmoPTA (3) (dmoPTA = 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) by elimination of the -CH(2)- group located between both NCH(3) units. Compound dmPTA(BF(4))(2) (2) and complex [RuClCp(HdmoPTA)(PPh(3))](OSO(2)CF(3)) (4) have also been synthesized, while compounds HdmoPTA(BF(4)) (3a) and [RuClCp(dmPTA)(PPh(3))](OSO(2)CF(3)) (5) were characterized but not isolated. The new ligands and the complex have been fully characterized by NMR, IR, elemental analysis, and X-ray crystal structure determination (ligand 1 and complex 4). The synthetic processes for 3 and 4 were studied.     

Antiproliferative activity of ruthenium and osmium clusters with phosphine ligands

New ruthenium and osmium carbonyl clusters with 1,3,5-triaza-7-phosphatricyclo-[3.3.1.13.7]decane and 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane ligands were synthesized using Me₃NO as an initiator. The data on antiproliferative activity of new compounds against ovarian carcinoma cell cultures A2780 (cisplatin-sensitive) and A2780cisR (cisplatin-resistant) are reported. The dependence of cytotoxicity on the number of phosphine ligands was demonstrated.     

Two new water-soluble derivatives of 1,3,5-triaza-7-phosphaadamantane (PTA): Synthesis,characterization, X-ray analysis and solubility studies of 3,7-diformyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane and 1-pyridylmethyl-3,5-diaza-1-azonia-7-phosphatricyclo[3.3.1.1]decane bromide

Two water-soluble phosphines, 3,7-diformyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (1, DFPTA) and 1-pyridylmethyl-3,5-diaza-1-azonia-7-phosphatricyclo[3.3.1.1]decane bromide (2, [pymePTA]Br), have been respectively, prepared by reacting 1,3,5-triaza-7-phosphaadamantane (PTA) with formic anhydride and bromomethylpyridine. Compound 1 is only the second acyl derivative of PTA to be prepared while 2 is only the second derivative of PTA reported that contains an aromatic appendage. Both compounds were characterized by elemental analysis, FAB-MS, ¹H, ¹³C, and ³¹P NMR spectroscopy, and single crystal X-ray diffraction. This analysis showed that the formamide groups of 1 were in an anti confirmation in solution but in a syn confirmation in the solid state. The solubilities of 1 and 2 were examined in common organic solvents and water. It was found that 1.1 M aqueous solutions of 1 could be prepared while 2.4 M solutions of 2 were produced. The greater solubility of 2 was likely due to its ionic nature.     

Thiolato gold(I) complexes containing water-soluble phosphane ligands: a characterization of their chemical and biological properties

A series of thiolate gold(I) derivatives bearing water soluble phosphanes--namely sodium triphenylphosphane monosulfonate (TPPMS), sodium triphenylphosphane trisulfonate (TPPTS), 1,3,5-triaza-7-phosphaadamantane (PTA) and 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA)--is reported and the compounds studied for their luminescence properties in the solid state. Two of these derivatives, [Au(SMe(2)pyrim)(PTA)] and [Au(SBenzoxazole)(DAPTA)], are also structurally characterized by X-ray diffraction analysis. Strong antiproliferative effects are observed for most of the compounds in the human ovarian carcinoma cell lines (A2780/S) and its cisplatin-resistant variant (A2780/R), which depend on both the type of thiolate and phosphane ligands. ICP-MS studies were also performed to evaluate the influence of the gold uptake on the cytotoxic potency of the compounds.     

Water-soluble 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (dmoPTA) as a polydentate ligand: synthesis of [RuClCp(PPh3)-mu-dmoPTA-1kappaP:2kappa2N,N'-Co(acac-kappa2O,O')2].H2O

The dinuclear complex [RuClCp(PPh3)-mu-dmoPTA-1kappa P:2kappa(2)N, N'-Co(acac-kappa(2)O, O') 2].H 2O (2; dmoPTA = 3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) has been synthesized by reaction of [RuClCp(HdmoPTA)(PPh3)](OSO2CF3) (1) with Co(acac)2 in methanol (HdmoPTA = 3,7-H-3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane). Elemental analysis, IR, NMR, and single-crystal X-ray structure determination have characterized the new complex. This complex is active for the catalytic isomerization of but-1-en-3-ol in acetone better than 1.     

Water-Soluble O-, S- and Se-Functionalized Cyclic Acetyl-triaza-phosphines. Synthesis,Characterization and Application in Catalytic Azide-alkyne Cycloaddition

The 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA) derivatives, viz. the already reported 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane 5-oxide (DAPTA=O, 1), the novel 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane-5-sulfide (DAPTA=S, 2), and 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane-5-selenide (DAPTA=Se, 3), have been synthesized under mild conditions. They are soluble in water and most common organic solvents and have been characterized using ¹H and ³¹P NMR spectroscopy and, for 2 and 3, also by single crystal X-ray diffraction. The effect of O, S, or Se at the phosphorus atom on the structural features of the compounds has been investigated, also through the analyses of Hirshfeld surfaces. The presence of 1–3 enhances the activity of copper for the catalytic azide-alkyne cycloaddition reaction in an aqueous medium. The combination of cheaply available copper (II) acetate and compound 1 has been used as a catalyst for the one-pot and 1,4-regioselective procedure to obtain 1,2,3-triazoles with high yields and according to ‘click rules’.     

Antitumor activity of new hydridotris(pyrazolyl)borate ruthenium(II) complexes containing the phosphanes PTA and 1-CH3-PTA

The synthesis and full characterization of new half-sandwich ruthenium(II) complexes containing κ(3)(N,N,N)-hydridotris(pyrazolyl)borate (κ(3)(N,N,N)-Tp) and the water-soluble phosphanes 1,3,5-triaza-7-phosphatricyclo[3.3.1.1(3,7)]decane (PTA) and 1-methyl-3,5-diaza-1-azonia-7-phosphatricyclo[3.3.1.1(3,7)]decane (1-CH(3)-PTA) has been explored. Single crystal X-ray diffraction analysis for complex [RuCl{κ(3)(N,N,N)-Tp}(PMe(2)Ph)(1-CH(3)-PTA)][CF(3)SO(3)]·2NCMe is also reported. DNA binding properties of the ruthenium complexes have been evaluated by mobility shift assay and MALDI-TOF mass spectrometry. The in vitro antitumor activity of these compounds was assessed by examining their ability to inhibit cell proliferation in a number of human cancer cell lines (NCI-H460, SF-268, MCF-7) and non-tumor human umbilical vein endothelial cells (HUVEC). Some of these new compounds show promising cytotoxic activity with IC(50) values in the low micromolar range, and display differential effects on cancer and normal cell growth.     

Synthesis, characterization, and in vitro cytotoxicity of some gold(I) and trans platinum(II) thionate complexes containing water-soluble PTA and DAPTA ligands. X-ray crystal structures of [Au(SC4H3N2)(PTA)], trans-[Pt(SC4H3N2)2(PTA)2], trans-[Pt(SC5H4N)2(PTA)2], and trans-[Pt(SC5H4N)2(DAPTA)2

A series of gold(I) and platinum(II) complexes of the type [Au(SR)(P)] and trans-[Pt(SR) 2(P) 2] [SR = 2-thiopyridine (SPy), 2-thiopyrimidine (SPyrim); P = 1,3,5-triaza-7-phosphaadamantane (PTA), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA)] were prepared and characterized, and their in vitro cytotoxicities against a panel of seven human cancer cell lines were evaluated. The highly water soluble gold(I) complexes [Au(SR)(P)] [P = PTA and SR = SPy ( 1), SPyrim ( 2); P = DAPTA and SR = SPy ( 3), SPyrim ( 4)] showed low cytotoxicity, while the platinum(II) complexes trans-[Pt(SR) 2(P) 2] [P = PTA and SR = SPyrim ( 5), SPy ( 6); P = DAPTA and SR = SPyrim ( 7), SPy ( 8)] demonstrated potent cytotoxicity for ovarian, colon, renal, and melanoma cancer cell lines on the basis of a comparison with ID 50 values for some established cytotoxic drugs. Single crystals of 2, 5, 6, and 8 suitable for X-ray structural characterization were obtained, and the study revealed the trans configuration for 5, 6, and 8 in their solid states.     

Diastereomerically enriched analogues of the water-soluble phosphine PTA. Synthesis of phenyl(1,3,5-triaza-7-phosphatricyclo[3.3.1.1(3,7)]dec-6-yl)methanol (PZA) and the sulfide PZA(S) and X-ray crystal structures of the oxide PZA(O) and [Cp*IrCl(2)(PZA)

A diastereomerically enriched analogue of 1,3,5-triaza-7-phosphaadamantane (PTA) was obtained by the reaction of PTA lithium salt with benzaldehyde to give the water-soluble derivative phenyl(1,3,5-triaza-7-phosphatricyclo[3.3.1.13,7]dec-6-yl)methanol (PZA, 1) as a mixture of two diastereoisomers. PZA derivatives phenyl(1,3,5-triaza-7-phospha-tricyclo[3.3.1.13,7]dec-6-yl)methanol sulfide [PZA(S), 2] and oxide [PZA(O), 3] were also synthesized. The latter was isolated in the solid state, and the X-ray crystal structure of a single diastereoisomer was obtained. Compound 1 was used as a k1-P monodentate ligand toward iridium(III) moieties, and the piano-stool complex [Cp*IrCl2(PZA)] (4) was obtained as a mixture of diastereoisomers both in solution and in the solid state.     

Evaluation of ligand effects in the modified cobalt hydroformylation of 1-octene. Crystal structures of [Co(L)(CO)3]2 (L = PA-C5, PCy3 and PCyp3)

A series of phosphine ligands with different electronic and steric properties were evaluated at fully modified conditions in cobalt catalysed hydroformylation of 1-octene. The steric demand of the ligands was based on the Tolman cone angle model covering a range of 132-175°. The electron donating ability was evaluated through the first order Se-P coupling constants as determined from the corresponding phosphine selenides covering a range of 672-752 Hz. Crystal structures of three phosphine modified cobalt dimers, [Co(CO)(3)(L)](2) (L = PA-C(5), PCy(3) and PCyp(3) with PA-C(5) = 1,3,5,7-tetramethyl-8-pentyl-2,4,6-trioxa-8-phosphatricyclo[3.3.1.1(3,7)]decane), are reported. The Phoban and Lim ligands (Phoban = mixture of 9-phosphabicyclo[3.3.1 and 4.2.1]nonane, Lim = 4,8-dimethyl-2-phosphabicyclo[3.3.1]nonane) resulted in systems about twice as active as most of the other ligands investigated, these ligands have a high Lewis basicity with (1)J(Se-P) values from 684-687 Hz. The linearity of the alcohol product in general decreased for the less electron donating ligands while no clear relationship was evident as a function of steric size. The parallel competing hydrogenation of 1-octene to octane varied from 9-15% for a cone angle range of 132-172°, but a sharp increase of up to 40% was observed for PA-C(5), PCy(3) and PCyp(3), all with cone angles > 169°. The catalytic behaviour provides evidence that is contrary to the dissociative substitution of CO by an alkene as the rate limiting step in all cases. For large symmetrical ligands, such as PA-C(5), PCy(3) and PCyp(3) the rate limiting step may move within the catalytic cycle and may now be situated at the carbonylation step where the chemoselectivity is also determined. The lack of clear correlation between the steric and electronic effect of the ligands and all catalytic parameters may serve as additional proof that the same system, especially in terms of the rate determining step, is not operative in all cases. The Phoban and Lim systems are superior with the highest reactivity and lowest alkene loss through hydrogenation. The unsymmetrical nature of the Phoban and Lim ligands may provide flexibility to adopt geometries inducing both high and low steric crowding, which may be a reason for its beneficial catalytic properties.     

The Interactions of Low Oxidation State Transition Metal Clusters with DNA: Potential Applications in Cancer Therapy

A series of ruthenium and platinum clusters have been examined for DNA binding activity in methanol-water and water solutions. The clusters [H₄Ru₄(C₆H₆)₄]²⁺and Ru₃(CO)₉(PTA)₃(PTA=1,3,5-triaza-7-phosphatricyclo[3.3.1.1] decane) proved to be most effective; the former is believed to cross link DNA and the latter possibly intercalates. These clusters are highly water soluble and combined with their DNA damaging activity and size represent potential anticancer drugs.     

Development of organometallic ruthenium-arene anticancer drugs that resist hydrolysis

With a view to develop drugs that could resist hydrolysis in aqueous media, organometallic arene-capped ruthenium(II) 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (RAPTA) complexes bearing chelating carboxylate ligands have been prepared and studied. The new complexes, Ru(eta6-cymene)(PTA)(C2O4) (1) and Ru(eta6-cymene)(PTA)(C6H6O4) (2), were found to be highly soluble and kinetically more stable than their RAPTA precursor that contains two chloride ligands in place of the carboxylate ligands. They were also able to resist hydrolysis in water and exhibited significantly lower pKa values. Importantly, they showed a similar order of activity in inhibiting cancer cell-growth proliferation (as determined by in vitro assays) and exhibited oligonucleotide binding characteristics (as evidenced by matrix-assisted laser desorption ionization mass spectrometry) similar to those of the RAPTA precursor, hence realizing a strategy for developing a new generation of stable and highly water-soluble RAPTA adducts.     

Tertiary phosphine abstraction from a platinum(II) coordination complex with SeCN: Crystal and molecular structures of SePTA and [SePTA-Me]I · CH3OH

Reacting [PtCl(PTA)₃]Cl(PTA = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1^3,7]decane) with KSeCN in aqueous or MeOH medium results in the abstraction of the PTA ligands to yield SePTA. The reaction also proceeds quantitatively by direct reaction of PTA and KSeCN in water or methanol. The methylated PTA ligand, [PTA-Me]I (1-methyl-1-azonia-3,5-diaza-7-phosphatricyclo[3.3.1.1^3,7]decane iodide), reacts accordingly with KSeCN, albeit significantly slower. The crystal structure of SePTA, 1, and [SePTA-Me]I · CH₃OH, 2, revealed PSe bond distances of 2.0991(19) and 2.100(2) Å, respectively. The first order phosphorous selenium coupling constants, ¹J_P-Se (D₂O), of 722 and 788 Hz for SePTA and [SePTA-Me]I, respectively, indicates the latter is significantly less electron rich.     

Coordination chemistry of 1,3,5-triaza-7-phosphaadamantane (PTA) and derivatives. Part II. The quest for tailored ligands,complexes and related applications

This review paper covers the recent developments (2004–2009) on the tailored synthetic modifications and related coordination chemistry of the water-soluble cage-like aminophosphine ligand 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane (PTA), together with the new applications in the fields of catalysis, material science and medicinal chemistry.     

Anthracene-tethered ruthenium(II) arene complexes as tools to visualize the cellular localization of putative organometallic anticancer compounds

Anthracene derivatives of ruthenium(II) arene compounds with 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (pta) or a sugar phosphite ligand, viz., 3,5,6-bicyclophosphite-1,2-O-isopropylidene-α-d-glucofuranoside, were prepared in order to evaluate their anticancer properties compared to the parent compounds and to use them as models for intracellular visualization by fluorescence microscopy. Similar IC(50) values were obtained in cell proliferation assays, and similar levels of uptake and accumulation were also established. The X-ray structure of [{Ru(η(6)-C(6)H(5)CH(2)NHCO-anthracene)Cl(2)(pta)] is also reported.     

Isomerization of trans-[Ru(PTA)4Cl2] to cis-[Ru(PTA)4Cl2] in water and organic solvent: revisiting the chemistry of [Ru(PTA)4Cl2

trans-[Ru(PTA)4Cl2] (trans-1), (PTA = 1,3,5-triaza-7-phosphatricyclo[3.3.1.13,7]decane) has been isolated and structurally characterized by X-ray crystallography. The structure reveals ruthenium in a slightly distorted-octahedral environment bound to two axial chlorides and four equatorial PTA ligands. In organic solvents, trans-1 undergoes a relatively clean isomerization to cis-1. In aqueous environments, trans-1 undergoes a more complicated transformation involving isomerization, protonation, and ligand substitution affording cis-1 and a series of structurally related molecules. From these results, we conclude that the synthesis of [Ru(PTA)4Cl2] (1) affords trans-1, not cis-1, as earlier reports suggest. The water-soluble hydride cis-[Ru(PTA)4H2] (2) has also been synthesized from the reaction of trans-[Ru(PTA)4Cl2] with excess sodium formate. Compound 2 is stable in deoxygenated water and undergoes H/D exchange with D2O (t1/2 approximately equal to 120 min, at 25 degrees C). The solid-state structures of both trans-1 and 2 are described.     

Synthesis and coordination chemistry of a novel bidentate phosphine: 6-(diphenylphosphino)-1,3,5-triaza-7-phosphaadamantane (PTA-PPh2)

The upper rim of 1,3,5-triaza-7-phosphaadamantane (PTA) has been modified for the first time. Lithiation of PTA, with n-butyllithium, resulted in deprotonation of an alpha-phosphorus methylene and the formation of 1,3,5-triaza-7-phosphaadamantane-6-yllithium (PTA-Li). The chiral chelating phosphine 6-(diphenylphosphino)-1,3,5-triaza-7-phosphaadamantane (PTA-PPh2) was synthesized, in racemic form, by the reaction of PTA-Li with ClPPh2. PTA-PPh2 has been fully characterized in solution by multinuclear NMR spectroscopy and mass spectrometry and in the solid state by X-ray crystallography. The 31P NMR spectrum contains a pair of doublets at -19.8 and -100.1 ppm (d, (2)J(PP) = 65 Hz). Unlike PTA, the new bidentate phosphine, PTA-PPh2, is insoluble in aqueous solutions. Two group 6 metal carbonyl complexes, [M(CO)4(PTA-PPh2)] (M = W and Mo), were synthesized by the addition of PTA-PPh2 to cis-[M(CO)4(pip)2] and characterized by NMR spectroscopy, IR spectroscopy, and X-ray crystallography. Also reported are the solid-state structures of cis-[W(CO)4PTA2], cis-[W(CO)4(PTA)(PPh3)], and [W(CO)4DPPM] (DPPM = diphenylphosphinomethane). PTA-PPh2 appears to be sterically similar to and slightly more electron-donating than DPPM.     

Developing iron nitrosyl complexes as NO donor prodrugs

A novel class of water-soluble iron nitrosyl complexes has been developed for use as NO donor prodrugs. To elaborate these NO prodrugs various water-soluble ligands were used such as P(CH2OH)3, 1,3,5-triaza-7-phosphatricyclo[3.3.1.1]decane (PTA), 1,2-bis[bis(hydroxymethyl)phosphino]ethane (HMPE), 1,2-bis[bis(hydroxymethyl)phosphino]benzene (TMBz), cysteamine, cysteamine hydrochloride, L-cysteine ethyl ester hydrochloride (LCEE) and pyrimidine-2-thiol (pyrim). The mononuclear complexes Fe(NO)2P(CH2OH)3Cl , Fe(NO)2(P(CH2OH)3)2, Fe(NO)2(PTA)2, Fe(NO)2HMPE , Fe(NO)2TMBz , [Fe(NO)2pyrimI] , [Fe(NO)3P(CH2OH)3][X] (X=PF6, SbF6, BF4) and the dinuclear species [Fe(NO)2S(CH2)2NH3Cl]2, [Fe(NO)2S(CH2)2NH3I2] , [Fe(NO)2LCEE]2 and [Fe(NO)2pyrim]2 were obtained. Complexes , , , , , , and are water-soluble. , and were identified as nitroxyl and , , , and as nitric oxide donors by applying an EPR NO-trap assay. To determine the amount of nitric oxide which was released from the nitric oxide donors, an additional electrochemical methodology was used. The equilibrium release or the trapping concentration of NO was also studied by a UV-vis method, which allowed the rate constant of NO release to be determined.     

Cu(I) complexes bearing the new sterically demanding and coordination flexible tris(3-phenyl-1-pyrazolyl)methanesulfonate ligand and the water-soluble phosphine 1,3,5-triaza-7-phosphaadamantane or related ligands

The new sterically hindered scorpionate tris(3-phenylpyrazolyl)methanesulfonate (Tpms(Ph))(-) has been synthesized and its coordination behavior toward a Cu(I) center, in the presence of 1,3,5-triaza-7-phosphaadamantane (PTA), N-methyl-1,3,5-triaza-7-phosphaadamantane tetraphenylborate ((mPTA)[BPh4]) or hexamethylenetetramine (HMT) has been studied. The reaction between Li(Tpms(Ph)) (1) and [Cu(MeCN)4][PF6] yields [Cu(Tpms(Ph))(MeCN)] (2) which, upon further acetonitrile displacement on reaction with PTA, HMT, or (mPTA)[BPh4], gives the corresponding complexes [Cu(Tpms(Ph))(PTA)] (3), [Cu(Tpms(Ph))(HMT)] (4), and [Cu(Tpms(Ph))(mPTA)][PF6] (5). All the compounds have been characterized by (1)H, (31)P, (13)C, COSY or HMQC-NMR, IR, elemental analysis, and single crystal X-ray diffraction. In the complexes (3) and (5), which bear a phosphine ligand (i.e., PTA and mPTA, respectively), the new scorpionate ligand shows the typical N, N, N-coordination mode, whereas in (2) and (4), bearing a N-donor ligand (i.e., MeCN and HMT, respectively), it binds the metal via the N,N,O chelating mode, involving the sulfonate moiety.     

Synthesis and characterisation of the water soluble bis-phosphine complex [Ru(η6-cymene)(PPh2(o-C6H4O)-κ2-P,O)(pta)]+ and an investigation of its cytotoxic effects

Metal complexes bearing phosphine ligands are attracting increasing attention for their applications in medicinal chemistry. In particular, organometallic ruthenium-phosphine complexes have been found to exhibit promising antitumour activity. The synthesis, anticancer activity and reactivity of a novel bis-phosphine complex, [Ru(η⁶-cymene)(PPh₂(o-C₆H₄O)-κ²-P,O)(pta)]Cl (pta = 1,3,5-triaza-7-phosphatricyclo[3.3.1.1.]decane), is presented. The complex appears to exhibit its anticancer effect via a different mechanism to other ruthenium-arene pta complexes with labile co-ligands.