Photoactivatable metal complexes : from theory to applications in biotechnology and medicine

This short review highlights some of the exciting new experimental and theoretical developments in the field of photoactivatable metal complexes and their applications in biotechnology and medicine. The examples chosen are based on some of the presentations at the Royal Society Discussion Meeting in June 2012, many of which are featured in more detail in other articles in this issue. This is a young field. Even the photochemistry of well-known systems such as metal–carbonyl complexes is still being elucidated. Striking are the recent developments in theory and computation (e.g. time-dependent density functional theory) and in ultrafast-pulsed radiation techniques which allow photochemical reactions to be followed and their mechanisms to be revealed on picosecond/nanosecond time scales. Not only do some metal complexes (e.g. those of Ru and Ir) possess favourable emission properties which allow functional imaging of cells and tissues (e.g. DNA interactions), but metal complexes can also provide spatially controlled photorelease of bioactive small molecules (e.g. CO and NO)—a novel strategy for site-directed therapy. This extends to cancer therapy, where metal-based precursors offer the prospect of generating excited-state drugs with new mechanisms of action that complement and augment those of current organic photosensitizers

Controlling platinum, ruthenium, and osmium reactivity for anticancer drug design

The main task of the medicinal chemist is to design molecules that interact specifically with derailed or degenerating processes in a diseased organism, translating the available knowledge of pathobiochemical and physiological data into chemically useful information and structures. Current knowledge of the biological and chemical processes underlying diseases is vast and rapidly expanding. In particular the unraveling of the genome in combination with, for instance, the rapid development of structural biology has led to an explosion in available information and identification of new targets for chemotherapy. The task of translating this wealth of data into active and selective new drugs is an enormous, but realistic, challenge. It requires knowledge from many different fields, including molecular biology, chemistry, pharmacology, physiology, and medicine and as such requires a truly interdisciplinary approach. Ultimately, the goal is to design molecules that satisfy all the requirements for a candidate drug to function therapeutically. Therapeutic activity can then be achieved by an understanding of and control over structure and reactivity of the candidate drug through molecular manipulation

The physical determinants of the thickness of lamellar polymer crystals

Based upon kinetic Monte Carlo simulations of crystallization in a simple polymer model we present a new picture of the mechanism by which the thickness of lamellar polymer crystals is constrained to a value close to the minimum thermodynamically stable thickness. This description contrasts with those given by the two dominant theoretical approaches.Comment: 4 pages, 4 figures, revte

Protein flexibility is key to cisplatin crosslinking in calmodulin

Chemical crosslinking in combination with Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) has significant potential for studying protein structures and proteinprotein interactions. Previously, cisplatin has been shown to be a crosslinker and crosslinks multiple methionine (Met) residues in apo-calmodulin (apo-CaM). However, the inter-residue distances obtained from nuclear magnetic resonance structures are inconsistent with the measured distance constraints by crosslinking. Met residues lie too far apart to be crosslinked by cisplatin. Here, by combining FTICR MS with a novel computational flexibility analysis, the flexible nature of the CaM structure is found to be key to cisplatin crosslinking in CaM. It is found that the side chains of Met residues can be brought together by flexible motions in both apo-CaM and calcium-bound CaM (Ca4-CaM). The possibility of cisplatin crosslinking Ca4-CaM is then confirmed by MS data. Therefore, flexibility analysis as a fast and low-cost computational method can be a useful tool for predicting crosslinking pairs in protein crosslinking analysis and facilitating MS data analysis. Finally, flexibility analysis also indicates that the crosslinking of platinum to pairs of Met residues will effectively close the nonpolar groove and thus will likely interfere with the binding of CaM to its protein targets, as was proved by comparing assays for cisplatin-modified/unmodified CaM binding to melittin. Collectively, these results suggest that cisplatin crosslinking of apo-CaM or Ca4-CaM can inhibit the ability of CaM to recognize its target proteins, which may have important implications for understanding the mechanism of tumor resistance to platinum anticancer drugs

Allosteric modulation of zinc speciation by fatty acids

Background: Serum albumin is the major protein component of blood plasma and is responsible for the circulatory transport of a range of small molecules that include fatty acids, hormones, metal ions and drugs. Studies examining the ligand-binding properties of albumin make up a large proportion of the literature. However, many of these studies do not address the fact that albumin carries multiple ligands (including metal ions) simultaneously in vivo. Thus the binding of a particular ligand may influence both the affinity and dynamics of albumin interactions with another. Scope of review: Here we review the Zn2 + and fatty acid transport properties of albumin and highlight an important interplay that exists between them. Also the impact of this dynamic interaction upon the distribution of plasma Zn2 +, its effect upon cellular Zn2 + uptake and its importance in the diagnosis of myocardial ischemia are considered. Major conclusions: We previously identified the major binding site for Zn2 + on albumin. Furthermore, we revealed that Zn2 +-binding at this site and fatty acid-binding at the FA2 site are interdependent. This suggests that the binding of fatty acids to albumin may serve as an allosteric switch to modulate Zn2 +-binding to albumin in blood plasma. General significance: Fatty acid levels in the blood are dynamic and chronic elevation of plasma fatty acid levels is associated with some metabolic disorders such as cardiovascular disease and diabetes. Since the binding of Zn2 + to albumin is important for the control of circulatory/cellular Zn2 + dynamics, this relationship is likely to have important physiological and pathological implications. This article is part of a Special Issue entitled Serum Albumin

Anti-colorectal cancer activity of an organometallic osmium arene azopyridine complex

This first in vivo antitumour activity for an organometallic osmium arene complex, [Os(eta(6)-p-cym)(4-(2-pyridylazo)-N,N-dimethylaniline)I]PF(6), is reported. The complex delays the growth of HCT116 human colon cancer xenografts in mice, with negligible toxicity. Its activity appears to involve redox mechanisms and its potency towards A2780 ovarian and A549 lung cancer cells is increased significantly in combination with L-buthionine-sulfoximine

A comparative analysis of place branding in Michigan and Ontario

Place branding has increasingly been adopted as a municipal initiative to change the trajectory of local economic development. Specifically, local municipalities and communities have used place branding not only as a response to the influence of globalization and neo-liberalism, but also economic challenges and restructuring. Like any other initiative, the ultimate goal is to enhance the economic and social well-being of local jurisdictions. Although a popular strategy, it is not clear if and how locally specific factors mediate the process. By comparing two cross-border geographical areas, this study attempts to identify how regional variability in the manifestation of politicaleconomic forces, as well as geographical influences, affects the use of place branding at local scales. Every municipality in Michigan (n = 1774) and Ontario (n = 414) was systematically examined for the presence and message of local place brands as presented through logos and slogans. The comparative analysis demonstrated that Ontario’s municipalities utilized place branding to a greater extent, and that the dominant messages differ by region. Further, this analysis shows that – beyond political differences – geographical context appears to have an effect on both local place branding usage and message

Global Campus: learning to walk with webbed feet

Universities wishing to expand their provision beyond their local catchment areas need to consider whether to bring the students to the tuition or take the tuition to the students. Current-day educational and information technologies make the latter option a much more achievable prospect than it has been in the past. Nevertheless, careful consideration needs to be given to the nature of the distance-learning students' learning experiences and the extent to which these may be comparable with those of the local students. These matters are considered in this paper against the background of the Global Campus project whereby Middlesex University's School of Computing Science sought to take its initial steps in distance-learning provision

Extended, regular HI structures around early-type galaxies

We discuss the morphology and kinematics of the HI of a sample of 30 southern gas-rich early-type galaxies selected from the HI Parkes All-Sky Survey (HIPASS). This is the largest collection of high-resolution HI data of a homogeneously selected sample. Given the sensitivity of HIPASS, these galaxies represent the most HI-rich early-type galaxies. In two-thirds of the galaxies, we find the HI to be in a large, regular disk- or ring-like structure that in some cases is strongly warped. In the remaining cases we find the HI distributed in irregular tails or clouds offset from the galaxy. The giant, regular HI structures can be up to ~200 kpc in diameter and contain up to 10^10 M_sun of HI. The incidence of irregular HI structures appears to be somewhat higher in elliptical galaxies, but the large, regular structures are observed in both elliptical and S0 galaxies and are not strictly connected to the presence of a stellar disk. If these two types of galaxies are the result of different formation paths, this is not strongly reflected in the characteristics of the HI. The size and the regular kinematics of the HI structures imply that the neutral hydrogen must have settled in these galaxies several Gyr ago. Merging as well as gas accretion from the IGM are viable explanations for the origin of the gas in these galaxies. The average column density of the HI is low so that little star formation is expected to occur and these early-type galaxies can remain gas rich for very long periods of time. The large HI structures likely represent key structures for tracing the origin and evolution of these galaxies.Comment: Accepted for publication in A&A, 13 pages, 6 figures. A version with full resolution figures is available at http://www.astron.nl/~morganti/Papers/hipass.pd