Strategies to eliminate tumor cells have long been sought. We envisioned that a small molecule could be used to decorate the offending cells with immunogenic carbohydrates and evoke an immune response. To this end, we describe the synthesis of bifunctional ligands possessing two functional motifs: one binds a cell-surface protein and the other binds a naturally occurring human antibody. Our conjugates combine an RGD-based peptidomimetic, to target cells displaying the alpha v beta3 integrin, with the carbohydrate antigen galactosyl-alpha(1-3)galactose [Galalpha(1-3)Gal or alpha-Gal]. To generate such bifunctional ligands, we designed and synthesized RGD mimetics 1 b and 2 c, which possess a free amino group for modification. These compounds were used to generate bifunctional derivatives 1 c and 2 d, with dimethyl squarate serving as the linchpin; thus, our synthetic approach is modular. To evaluate the binding of our peptidomimetics to the target alpha v beta3-displaying cells, we implemented a cell-adhesion assay. Results from this assay indicate that the designed, small-molecule ligands inhibit alpha v beta3-dependent cell adhesion. Additionally, our most effective bifunctional ligand exhibits a high degree of selectivity (4000-fold) for alpha v beta3 over the related alpha v beta5 integrin, a result that augurs its utility in specific cell targeting. Finally, we demonstrate that the bifunctional ligands can bind to alpha v beta3-positive cells and recruit human anti-Gal antibodies. These results indicate that both the integrin-binding and the anti-Gal-binding moieties can act simultaneously. Bifunctional conjugates of this type can facilitate the development of new methods for targeting cancer cells by exploiting endogenous antibodies. We anticipate that our modifiable alpha v beta3-binding ligands will be valuable in a variety of applications, including drug delivery and tumor targeting.

BackgroundFew studies compared radiographic and clinical outcomes between posterior dynamic stabilization (PDS) and posterior lumbar intervertebral fusion (PLIF) in treating degenerative disc disease (DDD).MethodsA total of 176 consecutive patients who underwent posterior instrumented spinal surgery for degenerative disc disease between January 2007 and January 2009 were prospectively divided into two groups—PDS and PLIF. All patients included in the analysis were followed up for 3 years. Demographic distribution, perioperative complications, and radiographic and clinical outcomes were compared between the two groups.ResultsThe amount of intraoperative blood loss and drained volume was significantly greater in the PLIF group compared with the PDS group (881.1 ml versus 737.4 ml, p = 0.004). The length of stay of patients who had PLIF surgery (20.9 days) was significantly longer (p = 0.033) than that of patients who underwent PDS surgery (18.9 days). Patients with PLIF surgery had higher total costs than those with PDS surgery (US$12826.8 versus US$11654.5, p = 0.002). No statistically significant differences existed in back visual analogue scale (VAS), leg VAS, or Oswestry disability index (ODI) scores between the PDS and PLIF groups of patients at each time point.ConclusionsCompared with PLIF, PDS have advantages on blood loss, length of stay in hospital, total charges, and radiographic outcomes, but no advantages on leg and back VAS or ODI scores. High-quality randomized controlled trials are still required in the future.

A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.

The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.