Richard J. Bowen

Role of lipophilicity in determining cellular uptake and antitumour activity of gold phosphine complexes

Purpose: The lipophilic cation [Au(I)(dppe)2]+ [where dppe is 1,2-bis(diphenylphosphino)ethane] has previously demonstrated potent in vitro antitumour activity. We wished to determine the physicochemical basis for the cellular uptake of this drug, as well as of analogues including the 1:2 adducts of Au(I) with 1,2-bis(di-n-pyridylphosphino)ethane (dnpype; n=2, 3 and 4), and to compare in vitro and in vivo antitumour activity. Methods and results: Logarithmic IC50 values for the CH-1 cell line bore a parabolic dependence on drug lipophilicity, as measured either by high-performance liquid chromatography or by n-octanol-water partition. Cellular uptake of drug, as measured by inductively coupled plasma mass spectrometry, varied by over three orders of magnitude over the series. Logarithmic uptake had a parabolic dependence on drug lipophilicity but a linear relationship to logarithmic IC50 values. Free drug concentrations were determined under the culture conditions and logarithmic free drug IC50 values and uptake rates were linearly related to lipophilicity. Uptake of drug in vivo in tissue from murine colon 38 tumours was approximately proportional to the dose administered. Host toxicity varied according to lipophilicity with the most selective compound having an intermediate value. This compound was also the most active of those tested in vivo, giving a growth delay of 9 days following daily intraperitoneal dosing (10 days) at 4 μmol kg−1 day−1. It was also significantly more active than another lipophilic cation, MKT-077. Conclusions: Alteration of lipophilicity of aromatic cationic antitumour drugs greatly affects cellular uptake and binding to plasma proteins. Changes in lipophilicity also affect host toxicity, and optimal lipophilicity may be a critical factor in the design of analogues with high antitumour activity.

Structural and Solution Chemistry of gold(I) and Silver(I) complexes of bidentate pyridyl phosphines: selective antitumour agents

Abstract The 1:2 adducts of Ag(I) and Au(I) with 1,2-bis(di- n -pyridylphosphino)ethane (d n pype) for n =2, 3 and 4 have been synthesised and solution properties characterised by multinuclear NMR spectroscopy. The complexes are hydrophilic analogs of the lipophilic Au(I) antitumour complex [Au(dppe) 2 ] + and the degree of hydrophilicity depends critically on the position of the N atom in the pyridyl ring. The complexes of d3pype and d4pype are simple monomeric [M(d3pype) 2 ] + and [M(d4pype) 2 ] + species which have a much higher water solubility than the 2-pyridyl complexes which crystallise in the solid state as dimeric [{M(d2pype) 2 } 2 ] 2+ . In solution these 1:2 M:d2pype species exist as equilibrium mixtures of monomeric, dimeric and trimeric (Ag) or tetrameric (Au) clusters. The Au(I) and Ag(I)pyridyl phosphine complexes have been evaluated for antitumour activity against a panel of cultured human ovarian carcinoma cell lines. The results show both potent and selective activity for the compounds with IC 50 values ranging from 0.18 to 1500 μM. There is a correlation between the degree of antitumour selectivity and the octanol/water partition coefficients with the greatest selectivity (500-fold range) found for the most hydrophilic complex [Au(d4pype) 2 ]Cl. Clinical development of the parent compound [Au(dppe) 2 ] + was halted by liver toxicity and the hydrophilic pyridylphosphine analogs are significantly less toxic than [Au(dppe) 2 ] + when exposed to isolated rat hepatocytes. Convenient synthetic routes to the bidentate pyridyl phosphines d2pype, d3pype and d4pype are also described.

Convenient synthetic routes to bidentate and monodentate 2-, 3- and 4-pyridyl phosphines: potentially useful ligands for water-soluble complex catalysts

The monodentate and bidentate pyridyl phosphines, PR3 and R2P(CH2)2PR2, where R=3- or 4-pyridyl can be prepared in high yields by treatment of butyllithium/TMEDA/3- or 4-bromopyridine with PCl3 or Cl2P(CH2)2PCl2 at low temperature. 1,2-Bis(di-2-pyridylphosphino)ethane is conveniently synthesised by an alternative route involving reaction of 1,2-dibromoethane with lithium di-2-pyridylphosphide.

1 : 2 Adducts of copper(I) halides with 1,2-bis(di-2-pyridylphosphino)ethane: solid state and solution structural studies and antitumour activity

The 1 : 2 adducts of copper(I) halides with 1,2-bis(2-pyridylphosphino)ethane (d2pype) have been synthesized and solution properties characterized by variable temperature (1)H, (31)P and (65)Cu NMR spectroscopy. Single-crystal structure determinations for the chloride, bromide and iodide complexes show these to crystallize from acetonitrile in the triclinic space group P1 as isostructural centrosymmetric dimers [(d2pype)Cu(mu-d2pype)(2)Cu(d2pype)]X(2).(solvent) with a approximately 12.6, b approximately 12.7, c approximately 15.3 A, alpha approximately 84, beta approximately 67, gamma approximately 84 degrees. In contrast to the analogous AuCl:2(d2pype) and AgNO(3):2(d2pype) adducts, in solution these CuX:2(d2pype) adducts (where X = Cl, Br and I) exist almost exclusively as bis-chelated monomeric [Cu(d2pype)(2)]X; evidence for an equilibrium between monomeric and dimeric forms is detected only for the CuCl adduct in methanol. Cytotoxicity studies in two human breast cancer lines and two matched liver progenitor cell lines indicate that [Cu(d2pype)(2)]Cl is non selectively toxic to both non-tumourigenic and tumourigenic cells. However, the analogous Au(I) compound [Au(d2pype)(2)]Cl, is toxic to highly tumourigenic cells and more selective in its toxicity to tumourigenic cells compared to non-tumourigenic cells. The significance of these results to the further development of selective, mitochondria-targeted, Au(I) antitumour complexes is discussed.

Tris(2-pyridyl)phosphine oxide: how C-H.O and C-H.N interactions can affect crystal packing efficiency.

Tris(2-pyridyl)phosphine oxide, (I), C(15)H(12)N(3)OP, is isomorphous with tris(2-pyridyl)phosphine. Because of a combination of C-H.O and C-H.N interactions, the crystal packing is denser in the title compound than in the related compounds triphenylphosphine oxide and tris(2-pyridyl)phosphine.

Synthesis and characterization of alkyltris(2-pyridyl)phosphonium salts

Alkytris(2-pyridyl)phosphonium salts [(2-Py) 3 PR]X 1 [1a, R = Et, X = Br; 1b, R = Pr, X = Br; 1c, R = Bu, X = Br; 1d, R = CH2Ph, X = Br; 1e, R = CH 2 Ph, X = Cl] were synthesised from (2-Py) 3 P and an excess of RCl. 1c and 1e were found to rapidly decompose in hot acetone to 2,2′-bipyridinium(+1) bromide 2 and (2-Py)P(O)(CH 2 Ph)C(OH)Me 2 3, respectively. A reaction mechanism for both products is proposed. All compounds were fully characterized, including X-ray crystallography for 1a and 3 with 1a being the first representative of this class of compounds characterized by this technique.

Bis(bis(diphenylphosphino)ethane)rhodium(I) tetraphenylborate

Faculty of Health, Human Services and AppliedScience, Southbank Institute of TAFE, SouthBrisbane, 4101 Queensland, AustraliaCorrespondence e-mail:meijboomr.sci@mail.uovs.ac.zaKey indicatorsSingle-crystal X-ray studyT = 173 KMean (C–C) = 0.003 A˚R factor = 0.031wR factor = 0.074Data-to-parameter ratio = 19.7For details of how these key indicators wereautomatically derived from the article, seehttp://journals.iucr.org/e.

Synthesis, Crystal Structures, and Reactions of 2-Oxomalonyl- bis(arylimidoyl) Chlorides and Hydroxymethane Tris(arylimidoyl) Chlorides

The 2-oxomalonylbis(arylimidoyl) chlorides [C6H3(R2-2,6)N=CCl]2CO (R = Me, 3a; Pri, 3b; H, 3c) were synthesized from C6H3(R2-2,6)NHCHO and an excess of (COCl2)3 and their reaction with various nucleophiles was studied. Successive hydrolysis of 3a led to the formation of [C6H3(Me2-2,6)N=CCl]3COH 4a and [C6H3(Me2-2,6)NHCO]3COH 5a, while treatment of 3a with HAuCl4(H2O)x gave {[C6H3(Me2-2,6)N(H)=CCl][C6H3(Me2-2,6)NHCO]2COH}AuCl4 6a. All compounds were fully characterized by microanalysis, NMR spectroscopy, mass spectrometry, and, in the case of 3a, 4a, 5a, and 6a, by X-ray crystallography.

1,2-Bis(di-4-pyridylphosphino)ethane (d4pype)

The title compound (d4pype), C22H20N4P2, crystallizes as a discrete molecular species disposed about a crystallographic inversion centre at the mid-point of the central C—C bond.

Synthesis and crystal structures of novel 1-aza-2-silacyclobut-3-enes

A crystallographic re-investigation of the structure of the 4-aryl(lithio)amino-1-aza-2-silacyclo-but-3-ene derivative, [Li{N(Ar)CC(R)SiR2NAr}](tmen) F (R = SiMe3, Ar = C6H3Me2-2,6), formed by the treatment of [Li(SiR3)(thf)3] with ArNC in the presence of tmen, revealed the presence of two independent molecules within the unit cell. Its protonolysis with cyclopentadiene monomer gave the 1-aza-2-silacyclobutene, HN(Ar)CC(R)Si(R)2NAr 2b. Replacing tmen with 1,2-bis(dimethylphosphino)ethane (dmpe), in the reaction of [Li(SiR3)(thf)3] with ArNC, gave either [Li{N(Ar)CC(R)Si(R)2NAr}(thf)2] 4 or the dimer [Li{N(Ar)CC(R)Si(R)2NAr}(μ-dmpe)]23, the latter being preferred at low thf concentrations. Each of the compounds F, 2b, 3 and 4 was characterised by multinuclear NMR spectroscopy and (not 4) X-ray diffraction. The single crystal structures of 2b and 3 provide the first examples of a neutral CCSiN compound and a neutral phosphine-bound alkali metal complex, respectively. The NMR spectra revealed that 3 undergoes speciation in solution.