Periodic trends within a series of five-coordinate thiolate-ligated [MII(SMe2N4(tren))]+ (M = Mn, Fe, Co, Ni, Cu, Zn) complexes, including a rare example of a stable CuII-thiolate.

A series of five-coordinate thiolate-ligated complexes [M(II)(tren)N4S(Me2)]+ (M = Mn, Fe, Co, Ni, Cu, Zn; tren = tris(2-aminoethyl)amine) are reported, and their structural, electronic, and magnetic properties are compared. Isolation of dimeric [Ni(II)(SN4(tren)-RS(dang))]2 ("dang"= dangling, uncoordinated thiolate supported by H bonds), using the less bulky [(tren)N4S](1-) ligand, pointed to the need for gem-dimethyls adjacent to the sulfur to sterically prevent dimerization. All of the gem-dimethyl derivatized complexes are monomeric and, with the exception of [Ni(II)(S(Me2)N4(tren)]+, are isostructural and adopt a tetragonally distorted trigonal bipyramidal geometry favored by ligand constraints. The nickel complex uniquely adopts an approximately ideal square pyramidal geometry and resembles the active site of Ni-superoxide dismutase (Ni-SOD). Even in coordinating solvents such as MeCN, only five-coordinate structures are observed. The MII-S thiolate bonds systematically decrease in length across the series (Mn-S > Fe-S > Co-S > Ni-S approximately Cu-S < Zn-S) with exceptions occurring upon the occupation of sigma* orbitals. The copper complex, [Cu(II)(S(Me2)N4(tren)]+, represents a rare example of a stable CuII-thiolate, and models the perturbed "green" copper site of nitrite reductase. In contrast to the intensely colored, low-spin Fe(III)-thiolates, the M(II)-thiolates described herein are colorless to moderately colored and high-spin (in cases where more than one spin-state is possible), reflecting the poorer energy match between the metal d- and sulfur orbitals upon reduction of the metal ion. As the d-orbitals drop in energy proceeding across the across the series M(2+) (M= Mn, Fe, Co, Ni, Cu), the sulfur-to-metal charge-transfer transition moves into the visible region, and the redox potentials cathodically shift. The reduced M(+1) oxidation state is only accessible with copper, and the more oxidized M(+4) oxidation state is only accessible for manganese.

Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography.

BACKGROUND: Numerous knockout mouse studies have revealed that P-glycoprotein (P-gp) significantly limits drug distribution across the mouse blood-brain barrier (BBB). To determine the importance of P-gp at the human BBB, we developed a state-of-the-art, noninvasive, quantitative imaging technique to measure P-gp activity by use of carbon 11-labeled verapamil as the P-gp substrate and cyclosporine (INN, ciclosporin) as the P-gp inhibitor. METHODS: In brief, 11C-verapamil (approximately 0.2 mCi/kg) was administered to healthy volunteers (n = 12 [6 women and 6 men]) as an intravenous infusion over a period of approximately 1 minute before and after at least a 1-hour infusion of cyclosporine (2.5 mg x kg(-1) x h(-1)). Arterial blood samples and brain positron emission tomography images were obtained at frequent intervals for 45 minutes. Both blood and plasma radioactivity contents were determined in each verapamil sample. The content of verapamil and its metabolites in the 20- and 45-minute plasma samples was determined by a rapid solid-phase extraction method. The brain uptake of 11C-radioactivity (brain area under the curve [AUCbrain ]/blood area under the curve [AUCblood]) was determined in the presence and absence of cyclosporine. RESULTS: The AUCbrain/AUCblood ratio of 11C-radioactivity was increased by 88% +/- 20% (1.02 +/- 0.18 versus 0.55 +/- 0.10, P < .001) in the presence of cyclosporine (mean blood concentration, 2.8 +/- 0.4 micromol/L) without affecting 11C-verapamil metabolism or plasma protein binding. The corresponding increases for the brain white and gray matter were 84% +/- 13% and 84% +/- 18%, respectively. CONCLUSIONS: This is the first time that P-gp activity at the human BBB has been measured. The modest inhibition of human BBB P-gp by cyclosporine has implications for P-gp-based drug interactions at the human BBB. Our method for imaging P-gp activity can be used to identify multidrug-resistant tumors or to determine the contribution of P-gp polymorphism, inhibition, or induction to interindividual variability in drug response.

Ligand oxidations in high-spin nickel thiolate complexes and zinc analogues.

Oxidations of a trigonal-bipyramidal, high-spin Ni(II) dithiolate complex of a pentadentate, N3S2-donor ligand, N1,N9-bis(imino-2-mercaptopropane)-1,5,9-triazanonane) nickel(II), and the structurally analogous Zn(II) complex, lead to oxidations of the ligand. Oxidation of the Ni(II) complex with I2 produces a novel Ni(II) macrocyclic cationic complex containing a monodentate disulfide ligand (2). Crystals of the I3- salt of the complex form in the triclinic space group P(1) with cell dimensions a=8.508(3) A, b=9.681(2) A, c=14.066(4) A, angles alpha=90.97(2) degrees , beta=91.61(3) degrees , gamma=90.83(2) degrees , and Z=2. The structure was refined to R=6.31% and Rw=16.63% (I > 2sigma(I)). Oxidation of the Ni(II) complex with O2 leads to the formation of a novel pentadentate bis-iminothiocarboxylate complex with trigonal-bipyramidal geometry (3). This neutral product crystallizes in the monoclinic space group P21/c with cell dimensions a=13.625(3) A, b=7.605(5) A, c=14.902(4) A, angles alpha=gamma=90 degrees, beta=102.81(2) degrees , and Z=4. The structure was refined to R=7.18% and Rw=17.86% (I > 2sigma(I)). Oxidation of the Zn(II) dithiolate analogue with O2 leads to the formation of the Zn(II) complex of the pentadentate bis-iminothiocarboxylate ligand. The neutral complex is isomorphous with the Ni(II) complex and crystallizes in the monoclinic space group P2(1)/c with cell dimensions a=13.8465(4) A, b=7.6453(2) A, c=15.0165(6) A, angles alpha=gamma=90 degrees , beta=103.2140(11) degrees , and Z=4. The structure was refined to R=3.96% and Rw=9.45% (I > 2sigma(I)). Details of the crystal structures are reported. Kinetics of the O2 reactions show that the reactions of the Ni(II) and Zn(II) dithiolates follow the rate law, Rate=k2[1][O2], with k2=1.81 M(-1) s(-1) for the Ni(II) complex and k2=1.93 x 10(-2) M(-1) s(-1) for the Zn(II) complex. The O2 oxidation of the high-spin Ni(II) thiolate complex was found to follow a similar oxidation mechanism to those of low-spin Ni(II) complexes, which form transient persulfoxide intermediates that yield S-oxidation products. In the case of the high-spin system reported here, the transient persulfoxide intermediate gives rise to an alternative ligand oxidation product, a bis-iminothiocarboxylate complex, because of the reactivity of the ligand, which contains a methylene with acidic H atoms alpha to the thiolate sulfur. The proposed mechanism is supported by studies of the analogous Zn dithiolate complex, which gives rise to the analogous bis-iminothiocarboxylate product (5).

PET measures of pre- and post-synaptic cardiac beta adrenergic function.

Positron Emission Tomography was used to measure global and regional cardiac beta-adrenergic function in 19 normal subjects and 9 congestive heart failure patients. [(11)C]-meta-hydroxyephedrine was used to image norepinephrine transporter function as an indicator of pre-synaptic function and [(11)C]-CGP12177 was used to measure cell surface beta-receptor density as an indicator of post-synaptic function. Pre-synaptic, but not post-synaptic, function was significantly different between normals and CHF patients. Pre-synaptic function was well matched to post-synaptic function in the normal hearts but significantly different and poorly matched in the CHF patients studied. This imaging technique can help us understand regional sympathetic function in cardiac disease.

Enhancing reactivity via structural distortion.

To examine how small structural changes influence the reactivity and magnetic properties of biologically relevant metal complexes, the reactivity and magnetic properties of two structurally related five-coordinate Fe(III) thiolate compounds are compared. (Et,Pr)-ligated [Fe(III)(S(2)(Me2)N(3)(Et,Pr))]PF(6) (3) is synthesized via the abstraction of a sulfur from alkyl persulfide ligated [Fe(III)(S(2)(Me2)N(3)(Et,Pr))-S(pers)]PF(6) (2) using PEt(3). (Et,Pr)-3 is structurally related to (Pr,Pr)-ligated [Fe(III)(S(2)(Me2)N(3)(Pr,Pr))]PF(6) (1), a nitrile hydratase model compound previously reported by our group, except it contains one fewer methylene unit in its ligand backbone. Removal of this methylene distorts the geometry, opens a S-Fe-N angle by approximately 10 degrees, alters the magnetic properties by stabilizing the S = 1/2 state relative to the S = 3/2 state, and increases reactivity. Reactivity differences between 3 and 1 were assessed by comparing the thermodynamics and kinetics of azide binding. Azide binds reversibly to both (Et,Pr)-3 and (Pr,Pr)-1 in MeOH solutions. The ambient temperature K(eq) describing the equilibrium between five-coordinate 1 or 3 and azide-bound 1-N(3) or 3-N(3) in MeOH is approximately 10 times larger for the (Et,Pr) system. In CH(2)Cl(2), azide binds approximately 3 times faster to 3 relative to 1, and in MeOH, azide dissociates 1 order of magnitude slower from 3-N(3) relative to 1-N(3). The increased on rates are most likely a consequence of the decreased structural rearrangement required to convert 3 to an approximately octahedral structure, or they reflect differences in the LUMO (vs SOMO) orbital population (i.e., spin-state differences). Dissociation rates from both 3-N(3) and 1-N(3) are much faster than one would expect for low-spin Fe(III). Most likely this is due to the labilizing effect of the thiolate sulfur that is trans to azide in these structures.