A novel anti-hepatitis B virus (anti-HBV) agent, 2-fluoro-5-methyl-␤-L-arabinofuranosyluracil (L-FMAU), was synthesized and found to be a potent anti-HBV and anti-Epstein-Barr virus agent. Its in vitro potency was evaluated in 2.2.15 and H1 cells for anti-HBV and anti-Epstein-Barr virus activities, respectively. In vitro cytotoxicity in MT2, CEM, 2.2.15, and H1 cells was also assessed, and the results indicated high antiviral selectivities of L-FMAU in these cells.A number of nucleosides have been reported to be antihepatitis B virus (anti-HBV) agents, although none of them have yet been proven to be clinically useful. As a part of our antiviral drug discovery program for HBV, we recently have reported the syntheses and anti-HBV activities of dioxolane (14, 15) and oxathiolane (1,8,13) nucleosides. (Ϫ)-␤-L-Dioxolane-cytosine has been found to be the most potent anti-HBV agent (50% effective concentration ϭ 0.0005 M in 2.2.15 cells), although the compound was the most toxic (50% inhibitory concentration ϭ 0.26 M in CEM cells) among those tested (15). Among the oxathiolane cytosine nucleosides we evaluated, (Ϫ)-␤-L-oxathiolane-cytosine has the most potent anti-HBV activity (50% effective concentration ϭ 0.01 M) and a favorable cytotoxicity (Ͼ50 M in CEM cells) (1). Interestingly, the (Ϫ)-␤-L isomer of this compound resisted deoxycytidine deaminase, while the (ϩ)-␤-D isomer was deaminated under similar conditions (3).Recently, an increasing number of L nucleosides have been reported to be antiherpesvirus (23), anti-human immunodeficiency virus (anti-HIV) (2,6,13,14,16,19), and anti-HBV (1,7,8,10,11,15,16) agents. Furthermore, some of the L nucleosides have been found to be more potent than the corresponding D nucleosides (6,13,14). Previously, 2Ј-fluoro-5-methyl-␤-D-arabinofuranosyluracil (FMAU) and 2Ј-fluoro-5-ethyl-␤-Darabinofuranosyluracil (FEAU) were reported (5, 24, 27) to be extremely potent antiviral agents against herpesvirus and HBV, respectively. However, the myelosuppression and neurotoxicity of FMAU limit its usefulness as a clinically effective antiviral agent. In view of the discovery that several nucleosides with the unnatural L configuration are selective antiviral agents, it was of interest to synthesize several 2Ј-fluoro-substituted (arabino configuration) nucleosides with the L configuration as potential antiviral agents, anticipating that these nucleosides will give lower toxicities than the corresponding D isomers. Thus, we report here the preliminary syntheses and antiviral activities of several pyrimidine nucleosides for which the corresponding D isomers have been known to exhibit potent antiviral activities.Synthesis. 1-O-Acetyl-2,3,5-tri-O-benzoyl-␤-L-ribofuranose (compound 1) was prepared from L-ribose (Fig. 1). The fully protected L-ribose compound 1 was selectively debenzoylated at the C-2 position and then was converted to the 2-fluorinated sugar (compound 3) according to the method described for the corresponding D isomer (25). The 2-fluorosugar (arabino configuration) compound 3 was c...

Glioblastoma multiforme is an aggressive, invasive brain tumour with a poor survival rate. Available treatments are ineffective and some tumours remain inoperable because of their size or location. The tumours are known to invade and migrate along white matter tracts and blood vessels. Here, we exploit this characteristic of glioblastoma multiforme by engineering aligned polycaprolactone (PCL)-based nanofibres for tumour cells to invade and, hence, guide cells away from the primary tumour site to an extracortical location. This extracortial sink is a cyclopamine drug-conjugated, collagen-based hydrogel. When aligned PCL-nanofibre films in a PCL/polyurethane carrier conduit were inserted in the vicinity of an intracortical human U87MG glioblastoma xenograft, a significant number of human glioblastoma cells migrated along the aligned nanofibre films and underwent apoptosis in the extracortical hydrogel. Tumour volume in the brain was significantly lower following insertion of aligned nanofibre implants compared with the application of smooth fibres or no implants.

Spinal cord injury (SCI) can lead to permanent motor and sensory deficits. Following the initial traumatic insult, secondary injury mechanisms characterized by persistent heightened inflammation are initiated and lead to continued and pervasive cell death and tissue damage. Anti-inflammatory drugs such as methylprednisolone (MP) used clinically have ambiguous benefits with debilitating side effects. Typically, these drugs are administered systemically at high doses, resulting in toxicity and paradoxically increased inflammation. Furthermore, these drugs have a small time window postinjury (few hours) during which they need to be infused to be effective. As an alternative to MP, we investigated the effect of a small molecule inhibitor (Chicago sky blue, CSB) of macrophage migration inhibitory factor (MIF) for treating SCI. The pleiotropic cytokine MIF is known to contribute to upregulation of several pro-inflammatory cytokines in various disease and injury states. In vitro, CSB administration alleviated endotoxin-mediated inflammation in primary microglia and macrophages. Nanocarriers such as liposomes can potentially alleviate systemic side effects of high-dose therapy by enabling site-specific drug delivery to the spinal cord. However, the therapeutic window of 100 nm scale nanoparticle localization to the spinal cord after contusion injury is not fully known. Thus, we first investigated the ability of nanocarriers of different sizes to localize to the injured spinal cord up to 2 weeks postinjury. Results from the study showed that nanocarriers as large as 200 nm in diameter could extravasate into the injured spinal cord up to 96 h postinjury. We then formulated nanocarriers (liposomes) encapsulating CSB and administered them intravenously 48 h postinjury, within the previously determined 96 h therapeutic window. In vivo, in this clinically relevant contusion injury model in rats, CSB administration led to preservation of vascular and white matter integrity, improved wound healing, and an increase in levels of arginase and other transcripts indicative of a resolution phase of wound healing. This study demonstrates the potential of MIF inhibition in SCI and the utility of nanocarrier-mediated drug delivery selectively to the injured cord.