J. Jonathan Harburn

Versatile routes to marine sponge metabolites through benzylidene rhodanines.

The first total synthesis of the marine natural products Psammaplin C and Tokaradine A is described. Benzylidene rhodanines were utilized as versatile intermediates toward the synthesis of seven brominated marine sponge metabolites through the optimization of protection group strategies. Spermatinamine demonstrated good inhibition of all cancer cell lines tested, in particular the leukemia K562 and colon cancer HT29 cell lines.

Synthesis and biological evaluation of purpurealidin E-derived marine sponge metabolites: aplysamine-2, aplyzanzine A, and suberedamines A and B.

Five purpurealidin-derived marine secondary sponge metabolies have been synthesized through the carbodiimide coupling of an appropriate bromotyrosine unit. The structure elucidations have been confirmed through direct comparison with spectroscopic data of isolated natural products. Aplyzanzine A has been shown to be the most active product against a broad bacterial and fungal screen, demonstrating MIC values 2 to 4 times lower than the other metabolites in this study. Compounds 2, 3, 4a, and 5-7 exhibit a modest inhibition against slow growing mycobacteria (MIC 25-50 μg/mL), including Mycobacterium tuberculosis. iso-Anomoian A and suberedamine B showed antitumor activity in the NCI-DTP60 cell line screen at single-digit micromolar concentrations, with iso-anomoian A inhibiting 53 cell lines. These molecules present novel scaffolds for further optimization.

SYNTHESIS OF NOVEL STEROIDAL INHIBITORS OF HIV-1 PROTEASE

The design and synthesis of potential steroidal HIV-1 protease inhibitors is described. Compounds derived from 11-amino-12-keto-cholanic acid derivatives show modest activity.

Magnetizable stent-grafts enable endothelial cell capture.

Emerging nanotechnologies have enabled the use of magnetic forces to guide the movement of magnetically-labeled cells, drugs, and other therapeutic agents. Endothelial cells labeled with superparamagnetic iron oxide nanoparticles (SPION) have previously been captured on the surface of magnetizable 2205 duplex stainless steel stents in a porcine coronary implantation model. Recently, we have coated these stents with electrospun polyurethane nanofibers to fabricate prototype stent-grafts. Facilitated endothelialization may help improve the healing of arteries treated with stent-grafts, reduce the risk of thrombosis and restenosis, and enable small-caliber applications. When placed in a SPION-labeled endothelial cell suspension in the presence of an external magnetic field, magnetized stent-grafts successfully captured cells to the surface regions adjacent to the stent struts. Implantation within the coronary circulation of pigs (n=13) followed immediately by SPION-labeled autologous endothelial cell delivery resulted in widely patent devices with a thin, uniform neointima and no signs of thrombosis or inflammation at 7 days. Furthermore, the magnetized stent-grafts successfully captured and retained SPION-labeled endothelial cells to select regions adjacent to stent struts and between stent struts, whereas the non-magnetized control stent-grafts did not. Early results with these prototype devices are encouraging and further refinements will be necessary in order to achieve more uniform cell capture and complete endothelialization. Once optimized, this approach may lead to more rapid and complete healing of vascular stent-grafts with a concomitant improvement in long-term device performance.

Magnetizable Duplex Steel Stents Enable Endothelial Cell Capture

Emerging medical nanotechnology applications often utilize magnetic forces to guide the movement of superparamagnetic particle linked cells and drugs in order to achieve a therapeutic effect. Superparamagnetic particle labeled endothelial cells have previously been captured on the surface of prototype nickel-plated stents in proof of concept studies. Facilitated endothelialization may help improve the healing of stented arteries and reduce the risk of stent thrombosis and restenosis. Extensive evaluation of candidate materials led to the development of a magnetizable 2205 duplex stainless steel stent. Magnetic field strengths of approximately 630 mG were induced within these stents by holding them in close proximity to a 0.7 T rare earth magnet. The magnetic field strength was reliably maintained over several days, but was partially reduced upon mild mechanical shock or plastic deformation. Mechanical testing demonstrated that stents could withstand crimping and expansion necessary for vascular implantation; however, magnetic field strength was significantly reduced. When placed in an endothelial cell suspension of 1×106 cells/mL, magnetized stents captured approximately 310 cells/mm2 compared to approximately 35 cells/mm2 for non-magnetized control stents. These data provide quantitative support to the observation that low level magnetization of stents may be adequate to attract labeled, autologous, blood-derived endothelial outgrowth cells following stent placement. This, in turn, may lead to more rapid and complete healing of stented arteries with a concomitant improvement in stent performance.

Cell Labeling and Targeting with Superparamagnetic Iron Oxide Nanoparticles.

Targeted delivery of cells and therapeutic agents would benefit a wide range of biomedical applications by concentrating the therapeutic effect at the target site while minimizing deleterious effects to off-target sites. Magnetic cell targeting is an efficient, safe, and straightforward delivery technique. Superparamagnetic iron oxide nanoparticles (SPION) are biodegradable, biocompatible, and can be endocytosed into cells to render them responsive to magnetic fields. The synthesis process involves creating magnetite (Fe3O4) nanoparticles followed by high-speed emulsification to form a poly(lactic-co-glycolic acid) (PLGA) coating. The PLGA-magnetite SPIONs are approximately 120 nm in diameter including the approximately 10 nm diameter magnetite core. When placed in culture medium, SPIONs are naturally endocytosed by cells and stored as small clusters within cytoplasmic endosomes. These particles impart sufficient magnetic mass to the cells to allow for targeting within magnetic fields. Numerous cell sorting and targeting applications are enabled by rendering various cell types responsive to magnetic fields. SPIONs have a variety of other biomedical applications as well including use as a medical imaging contrast agent, targeted drug or gene delivery, diagnostic assays, and generation of local hyperthermia for tumor therapy or tissue soldering.

Nanoparticle-Mediated Cell Capture Enables Rapid Endothelialization of a Novel Bare Metal Stent

Incomplete endothelialization of intracoronary stents has been associated with stent thrombosis and recurrent symptoms, whereas prolonged use of dual antiplatelet therapy increases bleeding-related adverse events. Facilitated endothelialization has the potential to improve clinical outcomes in patients who are unable to tolerate dual antiplatelet therapy. The objective of this study was to demonstrate the feasibility of magnetic cell capture to rapidly endothelialize intracoronary stents in a large animal model. A novel stent was developed from a magnetizable duplex stainless steel (2205 SS). Polylactic-co-glycolic acid and magnetite (Fe3O4) were used to synthesize biodegradable superparamagnetic iron oxide nanoparticles, and these were used to label autologous blood outgrowth endothelial cells. Magnetic 2205 SS and nonmagnetic 316L SS control stents were implanted in the coronary arteries of pigs (n = 11), followed by intracoronary delivery of magnetically labeled cells to 2205 SS stents. In this study, we show extensive endothelialization of magnetic 2205 SS stents (median 98.4% cell coverage) within 3 days, whereas the control 316L SS stents exhibited significantly less coverage (median 48.9% cell coverage, p < 0.0001). This demonstrates the ability of intracoronary delivery of magnetic nanoparticle labeled autologous endothelial cells to improve endothelialization of magnetized coronary stents within 3 days of implantation.

Dynamic covalent chemistry in fragment-based drug design.

In recent years Dynamic Covalent Chemistry (DCC) has transformed from being an academic curiosity to become an invaluable tool in the creation of functional systems. This contribution examines the role DCC has played over the past decade in Drug Discovery and, in particular, explores the synergy that has become apparent with Fragment Based Lead Discovery.

Steroid A-Ring Aromatisation of C-Ring Substituted 1,4-dien-3-ones

A number of A-ring steroidal 1,4-dien-3-ones 7, 8, 9 and 10 have been aromatised in zinc/pyridine–water; the products depend upon the position and type of C-ring substituents and provide new evidence in support of a radical anion mechanism.