Current Medicinal Chemistry - Volume 12, Issue 5, 2005

Analytical chemists have increasingly turned their attention to drug discovery and drug analysis and to solve fundamental questions of biological significance in physiology and genetics. New technologies have been developed, and a variety of instruments have been redesigned for biomedical applications. The development of high-performance liquid chromatography (HPLC) opened a new era in biorelated fields and allowed faster separations of fragile macromolecules. Capillary column gas chromatography (GC) / mass spectrometry (MS) have been used to achieve more powerful separation and to perform structural analysis of molecules, and laboratory automation including robotics has become a powerful trend in both analysis and synthesis. Liquid chromatography (LC) / MS is more suitable for biomedical applications than GC / MS because almost all biomolecules are heat sensitive. Furthermore, a combination of various mass spectrometers has been used even for proteins directly. Improving the sensitivity of nuclear magnetic resonance spectrometry (NMR) has permitted a direct connection with LC. Purification of biomolecules on-line by LC has been performed since the development of chip-electrophoresis, On the other hand, computational chemical analysis is a promising technique given the advancing the hardware and software for use in chemical fields. In this review, a combination of chromatography and computational chemistry for use in drug discovery studies is described. Fast LC analysis using a column switching technique was introduced for aromatic amino acid metabolites and guanidino compounds. Recent developments in related technologies are also included from review papers.

Oligosaccharides are linked to the protein surface and play roles in a number of biological events. Therefore, much attention is being paid to research to investigate the function of the oligosaccharides. In order to investigate the function of oligosaccharides, many synthetic approaches have been examined by synthesizing O-linked or N-linked glycopeptides. Synthesis of O-linked type oligosaccharides is relatively feasible compared to that of N-linked oligosaccharides, because the number of sugar components in the former oligosaccharides is small. In the biosynthesis of oligosaccharides, only N-linked oligosaccharide is reconstructed from the high mannose-type to the hybrid and complex types at the Golgi apparatus. This scientific question, namely, why only N-glycan should change its structure, has been paid much attention and convenient synthesis for both N-glycan and glycopeptide having N-glycans has been examined in order to study the role of N-glycan. In this review, we would introduce recent synthetic developments focusing on the synthesis of N-linked glycopeptides and its analogues.

Tetrahydropyridine (THP) moiety is a part of many biologically active systems. The discovery of the neurotoxic properties of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as well as numerous alkaloids, prompted extensive research on the synthesis and pharmacological properties of these compounds. The goal was extending the database for structure-activity relationship (SAR) studies. Consequently, many promising drug candidates were designed and a lot more are under clinical study. The current paper reviews the most popular approaches for the synthesis of THP derivatives. The pharmacological characteristics of some THP derivatives are summarized together with composite of the data from their in vitro, ex vivo and in vivo assays.

The article discusses the qualitative and quantitative determination of non-steroidal antiinflammatory drugs like salicin, salicylic acid, tenoxicam, ketorolac, piroxicam, tolmetin, naproxen, flurbiprofen, diclofenac and ibuprofen by reversed phase high performance liquid chromatography (RP-HPLC) and micro-HPLC (μ-HPLC) hyphenated with UV-absorbance and mass spectrometric detection. Both detection methods delivered calibration plots with good linearity (r2 < 0.9800), limits of detection in the low nanogram range and recovery rates between 94 and 104 %. For the analysis of biological samples such as blood, plasma and erythrocytes liquid-liquid extraction (LLE) and solid phase extraction (SPE) on the basis of new synthesized glycidylmethacrylate / divinylbenzene copolymer (GMA / DVB) particles and commercially available material on the basis of poly(divinylbenzene-co-N-vinylpyrrolidone) copolymer were investigated. Finally the use of a μ-HPLC system with separation columns in the range of 8 cm × 200 μm I.D. for the determination of non-steroidal anti-inflammatory drugs (NSAIDs) is presented, emphasizing on the type of column and sample amount needed.

Azapeptides, formed by replacing the Cα of amino acid residues by nitrogen, are promising peptidomimetic compounds. Azaamino acids impart a unique conformational property to peptide structures because of the loss of chirality and reduction of flexibility of the parent linear peptide. The peculiar conformational properties make azaamino acids an attractive tool for drug design involving specific secondary structures in peptides and proteins. Additionally, since azapeptides are less susceptible to enzymatic breakdown by proteases, they may possibly lead to orally active drugs with longer duration of action. One of the advantages of azapeptides is their unproblematic synthesis allowing retention of the amino acid side chain. Azapeptides have been developed by several groups for the design of hormone analogues, protease inhibitors and active site titrants.

Polyhalogenated aromatic arylhydrocarbons (PAHs) such as polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), the polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) are persistent lipophilic pollutants, which affect female fertility resulting in severe reproductive dysregulation, including anovulation, reduced conception rates, abortion, menstrual abnormalities and developmental defects of female reproductive tissues. Many PAHs exert their effects by activating a family of basic helix-loop-helix (bHLH) transcription factors, the arylhydrocarbon receptor (AhR) and the arylhydrocarbon receptor nuclear translocator (ARNT), which result in the expression of AhR target molecules. Complex interactions between PAH-mediated AhR activation and ER signalling pathways have been discovered which may contribute to the developmental malformations, impact on reproductive dysfunctions and promote carcinogenic dedifferentiation of tissues within the female reproductive tract. This review will focus on the multifaceted roles of PAHs in key organs of the female reproductive tract, the ovary, uterus/ endometrium and the mammary gland. The complexity and diversity of actions unleashed by PAHs in these female reproductive tissues identify these environmental pollutants as important endocrine disrupting toxicants impacting on female fertility.

Analogs of the excitatory neurotransmitter glutamate are potential medicinal agents for a wide variety of neurological disorders. The isoxazole glutamate derivatives represent an important class of compounds because of their receptor specificity and binding affinity. Since the discovery of (S)-2-amino-3-(3- hydroxy-5-methyl-4-isoxazolyl) propionic acid (AMPA) in 1980, numerous analogs built around the isoxazole scaffold have shown remarkable selectivity for specific ionotropic glutamate receptors, but strong side effects in human clinical trials have shown the need for improvement. Trends revealed by structure activity relationship and crystallographic studies indicate the role of stereochemistry may be important in uncovering the prerequisite selectivity, which would give rise to effective therapeutics for neurological dysfunction of the glutamate receptor.