Molecular docking-guided synthesis of NSAID-glucosamine bioconjugates and their evaluation as COX-1/COX-2 inhibitors with potentially reduced gastric toxicity.

Non-steroidal anti-inflammatory drugs (NSAIDs) are a powerful class of inhibitors targeting two isoforms of the family of cyclooxygenase enzymes (COX-1 and COX-2). While NSAIDs are widely used in the management of pain, in particular as a treatment for osteo- and rheumatoid arthritis, their long-term use has been associated with numerous on- and off-target effects. As the carboxylic acid moiety present in common NSAIDs is responsible for some of their adverse effects, but is not required for their anti-inflammatory activity, we sought to mask this group through direct coupling to glucosamine, which is thought to prevent cartilage degradation. We report herein the conjugation of commonly prescribed NSAIDs to glucosamine hydrochloride and the use of molecular docking to show that addition of the carbohydrate moiety to the parent NSAID can enhance binding in the active site of COX-2. In a preliminary, in vitro screening assay, the diclofenac-glucosamine bioconjugate exhibited 10-fold greater activity toward COX-2, making it an ideal candidate for future in vivo studies. Furthermore, in an intriguing result, we observed that the mefenamic acid-glucosamine bioconjugate displayed enhanced activity toward COX-1 rather than COX-2.

Glycoconjugate vaccines.

INTRODUCTION: The global disease burden of serious bacterial infections is caused mainly by Haemophilus influenzae type b (Hib), Streptococcus pneumoniae and Neisseria meningitidis. Death or disability may be the potential aftermath of invasive infections with these pathogens. Active immunisation is the only rational approach in preventing such infections. AREAS COVERED: This review discusses the immunology of vaccination and describes the immunogenicity, safety and impact of glycoconjugate vaccines that have been developed against Hib, the most prevalent serotypes of S. pneumoniae and N. meningitidis serogroups A, C, W-135 and Y in all ages. The immune response to the plain polysaccharide vaccines that target the same pathogens is compared to that induced by the respective glycoconjugate vaccine formulations. EXPERT OPINION: Continued surveillance is necessary to recognise any epidemiological changes influenced by the impact of glycoconjugate vaccines and is crucial in guiding future vaccination strategies. Although, in general, the immunogenicity of glycoconjugate vaccines results in robust immune responses in all ages, subsequent booster doses may be necessary to sustain protection. Challenges in addressing inequities in vaccine availability between industrialised and developing countries are still there. The limitations of plain polysaccharide vaccines make immunisation with glycoconjugates a more sustainable long term option.

Phase I and pharmacokinetic study of Bay 38-3441, a camptothecin glycoconjugate, administered as a 30-minute infusion daily for five days every 3 weeks in patients with advanced solid malignancies.

Bay 38-3441 is a camptothecin glycoconjugate which stabilizes the active lactone form of camptothecin and allows selective uptake into tumor cells. We conducted a phase I study of Bay 38-3441 administered as a 30-minute infusion daily for five consecutive days every 21 days. Thirty-one patients were enrolled at 8 dose levels. Most common nonhematologic side effects were diarrhea (29%), vomiting (19%), nausea (19%), lethargy (13%), and abdominal pain (10%). The main hematologic toxicity was prolonged neutropenia. Nine patients had a best response of stable disease with a median duration of 2.7 months (range: 2.3-20.6 months). The study was closed without reaching the maximum tolerated dose (MTD) due to excessive toxicity in a companion trial resulting in termination of development of this agent. Bay 38-3441 was well tolerated in this study with granulocytopenia as the main hematologic toxicity. This study showed that glycoconjugation is a feasible delivery technique for camptothecin.