Fibrillation of transferrin.

Background: The nature of fibrillar deposits from aqueous solutions of human serum and recombinant human transferrin on mica and carbon-coated formvar surfaces has been investigated.

Methods And Results: Atomic force microscopy showed that the deposition of recombinant transferrin onto the hydrophilic surface of mica resulted in the formation of a monolayer-thick film composed of conformationally-strained flattened protein molecules. Elongated fibres developed on top of this layer and appeared to be composed of single proteins or small clusters thereof.

Calibrating the end-Permian mass extinction.

The end-Permian mass extinction was the most severe biodiversity crisis in Earth history. To better constrain the timing, and ultimately the causes of this event, we collected a suite of geochronologic, isotopic, and biostratigraphic data on several well-preserved sedimentary sections in South China. High-precision U-Pb dating reveals that the extinction peak occurred just before 252.

Use of top-down and bottom-up Fourier transform ion cyclotron resonance mass spectrometry for mapping calmodulin sites modified by platinum anticancer drugs.

Calmodulin (CaM) is a highly conserved, ubiquitous, calcium-binding protein; it binds to and regulates many different protein targets, thereby functioning as a calcium sensor and signal transducer. CaM contains 9 methionine (Met), 1 histidine (His), 17 aspartic acid (Asp), and 23 glutamine acid (Glu) residues, all of which can potentially react with platinum compounds; thus, one-third of the CaM sequence is a possible binding target of platinum anticancer drugs, which represents a major challenge for identification of specific platinum modification sites. Here, top-down electron capture dissociation (ECD) was used to elucidate the transition metal-platinum(II) modification sites.

Reactions of an organoruthenium anticancer complex with 2-mercaptobenzanilide--a model for the active-site cysteine of protein tyrosine phosphatase 1B.

The organometallic anticancer complex [(η(6)-p-cymene)Ru(en)Cl]PF(6) (1, en = ethylenediamine) readily reacts with thiols and forms stable sulfenate/sulfinate adducts which may be important for its biological activity. Protein tyrosine phosphatase 1B (PTP1B), a therapeutic target, contains a catalytic cysteinyl thiol and is involved in the regulation of insulin signaling and the balance of protein tyrosine kinase activity. On oxidation, the catalytic Cys215 can form an unusual sulfenyl-amide intermediate which can subsequently be reduced by glutathione.

Probing platinum azido complexes by 14N and 15N NMR spectroscopy.

Metal azido complexes are of general interest due to their high energetic properties, and platinum azido complexes in particular because of their potential as photoactivatable anticancer prodrugs. However, azido ligands are difficult to probe by NMR spectroscopy due to the quadrupolar nature of (14)N and the lack of scalar (1)H coupling to enhance the sensitivity of the less abundant (15)N by using polarisation transfer. In this work, we report (14)N and (15)N NMR spectroscopic studies of cis,trans,cis-[Pt(N(3))(2)(OH)(2)(NH(3))] (1) and trans,trans,trans-[Pt(N(3))(2)(OH)(2)(X)(Y)], where X=Y=NH(3) (2); X=NH(3), Y=py (3) (py=pyridine); X=Y=py (4); and selected Pt(II) precursors.

Insights into the acid-base properties of Pt(IV)-diazidodiam(m)inedihyroxido complexes from multinuclear NMR spectroscopy.

Platinum(IV) am(m)ine complexes are of interest as potential anticancer pro-drugs, but there are few reports of their acid-base properties. We have studied the acid-base properties of three photoactivatable anticancer platinum(IV)-diazidodiam(m)ine complexes (cis,trans,cis-[Pt(IV)(N(3))(2)(OH)(2)(NH(3))(2)], trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(NH(3))(2)], and cis,trans-[Pt(IV)(N(3))(2)(OH)(2)(en)]) using multinuclear NMR methods and potentiometry. In particular, the combination of both direct and indirect techniques for the detection of (15)N signals has allowed changes of the chemical shifts to be followed over the pH range 1-11; complementary (14)N NMR studies have been also carried out.

Structure-activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity.

We report the synthesis and characterisation of 32 half sandwich phenylazopyridine Os(II) arene complexes [Os(η(6)-arene)(phenylazopyridine)X](+) in which X is chloride or iodide, the arene is p-cymene or biphenyl and the pyridine and phenyl rings contain a variety of substituents (F, Cl, Br, I, CF(3), OH or NO(2)). Ten X-ray crystal structures have been determined. Cytotoxicity towards A2780 human ovarian cancer cells ranges from high potency at nanomolar concentrations to inactivity.

Photocontrolled DNA binding of a receptor-targeted organometallic ruthenium(II) complex.

A photoactivated ruthenium(II) arene complex has been conjugated to two receptor-binding peptides, a dicarba analogue of octreotide and the Arg-Gly-Asp (RGD) tripeptide. These peptides can act as "tumor-targeting devices" since their receptors are overexpressed on the membranes of tumor cells. Both ruthenium-peptide conjugates are stable in aqueous solution in the dark, but upon irradiation with visible light, the pyridyl-derivatized peptides were selectively photodissociated from the ruthenium complex, as inferred by UV-vis and NMR spectroscopy.

Prevalence of hepatitis B infection among young and unsuspecting Hmong blood donors in the Central California Valley.

Chronic hepatitis B virus (HBV) infection may result in cirrhosis and/or hepatocellular carcinoma and is one of the leading causes of mortality in Asian Americans including Hmong Americans. The Central California Valley is home to a huge Hmong population. To date, the true prevalence of HBV among Hmong is largely unknown.

Organometallic -Dichlorido Ruthenium(II) Ammine Complexes.

Bifunctional neutral half-sandwich Ru complexes of the type [(η-arene)Ru(NH)Cl] where arene is -cym () or bip () were synthesised by the reaction of ,-dimethylbenzylamine (dmba), NHPF and the corresponding Ru arene dimer, and were fully characterised. X-ray crystallographic studies of [(η--cym)Ru(NH)Cl]{(dmba-H)(PF)} () and [(η-bip)Ru(NH)Cl] () show extensive H-bond interactions in the solid state, mainly involving the NH and the Cl ligands, as well as weak aromatic stacking interactions. The half-lives for the sequential hydrolysis of and determined by UV/Vis spectroscopy at 310 K ranged from a few minutes for the first aquation to ca.

Contrasting reactivity and cancer cell cytotoxicity of isoelectronic organometallic iridium(III) complexes.

Replacing the N,N-chelating ligand 2,2'-bipyridine (bpy) in the Ir(III) pentamethylcyclopentadienyl (Cp*) complex [(η(5)-C(5)Me(5))Ir(bpy)Cl](+) (1) with the C,N-chelating ligand 2-phenylpyridine (phpy) to give [(η(5)-C(5)Me(5))Ir(phpy)Cl] (2) switches on cytotoxicity toward A2780 human ovarian cancer cells (IC(50) values of >100 μM for 1 and 10.8 μM for 2). Ir-Cl hydrolysis is rapid for both complexes (hydrolysis equilibrium reached in <5 min at 278 K).

Mass spectrometry evidence for cisplatin as a protein cross-linking reagent.

Cisplatin is a potent anticancer drug, which functions by cross-linking adjacent DNA guanine residues. However within 1 day of injection, 65-98% of the platinum in the blood plasma is protein-bound. It is generally accepted that cisplatin binds to methionine and histidine residues, but what is often underappreciated is that platinum from cisplatin has a 2+ charge and can form up to four bonds.

The anticancer drug cisplatin can cross-link the interdomain zinc site on human albumin.

Cisplatin, cis-[Pt(Cl(2)(NH(3))(2)], can crosslink residues His67 of domain I and His247 of domain II in human albumin, occupying the major binding site for the essential metal zinc on the protein.

Differences in the cellular response and signaling pathways between cisplatin and monodentate organometallic Ru(II) antitumor complexes containing a terphenyl ligand.

The new monofunctional Ru(II)-arene complex [(η⁶-arene)Ru(II)(en)Cl]+, where en = 1,2-diaminoethane and the arene is para-terphenyl (complex 1) exhibits promising cytotoxic effects in human tumor cells including those resistant to conventional cisplatin (J. Med. Chem.

Identification of two reactive cysteine residues in the tumor suppressor protein p53 using top-down FTICR mass spectrometry.

The tumor suppressor p53 is a redox-regulated transcription factor involved in cell cycle arrest, apoptosis and senescence in response to multiple forms of stress, as well as many other cellular processes such as DNA repair, glycolysis, autophagy, oxidative stress and differentiation. The discovery of cysteine-targeting compounds that cause re-activation of mutant p53 and the death of tumor cells in vivo has emphasized the functional importance of p53 thiols. Using a combination of top-down and middle-down FTICR mass spectrometry, we show that of the 10 Cys residues in the core domain of wild-type p53, Cys182 and Cys277 exhibit a remarkable preference for modification by the alkylating reagent N-ethylmaleimide.

Influence of pyridine versus piperidine ligands on the chemical, DNA binding and cytotoxic properties of light activated trans,trans,trans-[Pt(N3)2(OH)2(NH3)(L)].

The photocytotoxicity and photobiochemical properties of the new complex trans,trans,trans-[Pt(N(3))(2)(OH)(2)(NH(3))(piperidine)] (5) are compared with its analogue containing the less basic and less lipophilic ligand pyridine (4). The log P (n-octanol/water) values were of -1.16 and -1.

Metal complexes as DNA intercalators.

DNA has a strong affinity for many heterocyclic aromatic dyes, such as acridine and its derivatives. Lerman in 1961 first proposed intercalation as the source of this affinity, and this mode of DNA binding has since attracted considerable research scrutiny. Organic intercalators can inhibit nucleic acid synthesis in vivo, and they are now common anticancer drugs in clinical therapy.

Organometallic half-sandwich iridium anticancer complexes.

The low-spin 5d(6) Ir(III) organometallic half-sandwich complexes [(η(5)-Cp(x))Ir(XY)Cl](0/+), Cp(x) = Cp*, tetramethyl(phenyl)cyclopentadienyl (Cp(xph)), or tetramethyl(biphenyl)cyclopentadienyl (Cp(xbiph)), XY = 1,10-phenanthroline (4-6), 2,2'-bipyridine (7-9), ethylenediamine (10 and 11), or picolinate (12-14), hydrolyze rapidly. Complexes with N,N-chelating ligands readily form adducts with 9-ethylguanine but not 9-ethyladenine; picolinate complexes bind to both purines. Cytotoxic potency toward A2780 human ovarian cancer cells increases with phenyl substitution on Cp*: Cp(xbiph) > Cp(xph) > Cp*; Cp(xbiph) complexes 6 and 9 have submicromolar activity.

Functionalization of osmium arene anticancer complexes with (poly)arginine: effect on cellular uptake, internalization, and cytotoxicity.

Attaching peptides to metallodrugs may result in improved biological properties of the complexes. The potential use of cell penetrating peptides (CPPs) as cell delivery vectors is attractive, since directed cell uptake of (metallo)drugs remains a major challenge in anticancer drug design. In this work, we report the synthesis of peptide conjugates of the organometallic Os(II) anticancer complex [(η(6)-biphenyl)Os(picolinate)Cl] with different arginine (Arg) chain lengths.

Photoreaction pathways for the anticancer complex trans,trans,trans-[Pt(N3)2(OH)2(NH3)2].

The photodecomposition of the anticancer complex trans,trans,trans-[Pt(N(3))(2)(OH)(2)(NH(3))(2)] in acidic aqueous solution, as well as in phosphate-buffered saline (PBS), induced by UVA light (centred at λ = 365 nm) has been studied by multinuclear NMR spectroscopy. We show that the photoreaction pathway in PBS, which involves azide release, differs from that in acidic aqueous conditions, under which N(2) is a major product. In both cases, a number of trans-{N-Pt(II/IV)-NH(3)} species were also observed as photoproducts, as well as the evolution of O(2) and release of free ammonia with a subsequent increase in pH.

Photo-induced pyridine substitution in cis-[Ru(bpy)(2)(py)(2)]Cl(2): a snapshot by time-resolved X-ray solution scattering.

Determination of transient structures in light-induced processes is a challenging goal for time-resolved techniques. Such techniques are becoming successful in detecting ultrafast structural changes in molecules and do not require the presence of probe-like groups. Here, we demonstrate that TR-WAXS (Time-Resolved Wide Angle X-ray Scattering) can be successfully employed to study the photochemistry of cis-[Ru(bpy)(2)(py)(2)]Cl(2), a mononuclear ruthenium complex of interest in the field of photoactivatable anticancer agents.

Organometallic osmium arene complexes with potent cancer cell cytotoxicity.

Iodido osmium(II) complexes [Os(η(6)-arene)(XY)I](+) (XY = p-hydroxy or p-dimethylaminophenylazopyridine, arene = p-cymene or biphenyl) are potently cytotoxic at nanomolar concentrations toward a panel of human cancer cell lines; e.g., IC(50) = 140 nM for [Os(η(6)-bip)(azpy-NMe(2))I](+) toward A2780 ovarian cancer cells.

Photoactivation of trans diamine platinum complexes in aqueous solution and effect on reactivity towards nucleotides.

We show that UVA irradiation (365nm) of the Pt(IV) complex trans,trans,trans-[Pt(IV)Cl(2)(OH)(2)(dimethylamine)(isopropylamine)] (1), induces reduction to Pt(II) photoproducts. For the mixed amine Pt(II) complex, trans-[Pt(II)Cl(2)(isopropylamine)(methylamine)] (2), irradiation at 365nm increases the rate and extent of hydrolysis, triggering the formation of diaqua species. Additionally, irradiation increases the extent of reaction of complex 2 with guanosine-5'-monophosphate and affords mainly the bis-adduct, while reactions with adenosine-5'-monophosphate and cytidine-5'-monophosphate give rise only to mono-nucleotide adducts.

Disturbed expression of the T-cell receptor/CD3 complex and associated signaling molecules in CD30+ T-cell lymphoproliferations.

Background: CD30(+) T-cell lymphoproliferations comprise a spectrum of clinically heterogeneous entities, including systemic anaplastic large cell lymphomas (ALK(-) and ALK(+)) and primary cutaneous CD30(+) T-cell lymphoproliferative disorders. While all these entities are characterized by proliferation of highly atypical, anaplastic CD30(+) T cells, the expression of T-cell specific antigens in the tumor cells is not consistently detectable.

Design And Methods: We evaluated biopsies from 19 patients with primary cutaneous CD30(+) lymphoproliferative disorders, 38 with ALK(-) and 33 with ALK(+) systemic anaplastic large cell lymphoma.