Is combinatorial chemistry on the right track for drug discovery?

Critical to the effective implementation of high throughput methods of synthesis is the necessity for a significant supporting level of automation. There are a number of critical issues associated with the successful introduction, and supporting role, of automation of small molecule chemical synthesis. Clearly there are needs for automation to increase drug candidate synthesis throughput. Automation of repetitive and laborious tasks associated with the synthesis process can release skilled chemists to apply their talents to the more challenging investigational aspects of developing new synthetic protocols. This provides continuity in the compound supply pipeline and ensures an optimal use of the automated platform for compound production. The very high fidelity of performing repetitive processes that can be managed through automation also removes some of the limitations and errors associated with more fallible human operators. This can include very difficult tasks associated with tracking data, and general information and inventory management. Taken collectively, these attributes associated with automation can lead to greater efficiencies, throughputs and improved allocation of human resources with concomitant reductions in costs associated with current day and future drug discovery. In our library development/synthesis paradigm, we feel that automation support must be invoked early in the process and that this automation support must continue throughout the project.     

SERS assisted ultra-fast peptidic screening: a new tool for drug discovery

Herein we present a direct label-free ultra-fast method for the identification and classification of the active members of a combinatorial library directly on the solid support used for their synthesis. The method is based on the appropriate functionalization of polyethylene glycol grafted polystyrene (TentaGel?) microbeads with Au@Ag nanoparticles, the use of these materials directly as solid-phase supports for the synthesis of combinatorial libraries of peptides and the subsequent SERS analysis for identification of each peptide on each bead.     

Computational chemistry, data mining, high-throughput synthesis and screening - informatics and integration in drug discovery

Drug discovery today includes considerable focus of laboratory automation and other resources on both combinatorial chemistry and high-throughput screening, and computational chemistry has been a part of pharmaceutical research for many years. The real benefit of these technologies is beyond the exploitation of each individually. Only recently have significant efforts focused on effectively integrating these and other discovery disciplines to realize their larger potential. This technical note will describe one example of these integration efforts.     

Carbohydrates as scaffolds in drug discovery

Drug discovery has long suffered from the difficulty of having to place pharmacophoric groups in just the right spatial arrangement to elicit the desired biological response. Although some molecule classes have been discovered that seem to be privileged structures for at least some drug-receptor interactions, there remains the challenge to design and synthesize molecules with high specific affinity to pharmacologically important targets. With their high density of stereochemical information and their relative rigidity, carbohydrates provide excellent platforms upon which to display a number of substituents in a sterically defined way, hence offering the opportunity to harness their unique features for the drug-discovery process. This review highlights the progress that has been made in the development of carbohydrate scaffolds for drug discovery.     

药物研发中特种试剂现状

简要地阐述了近几年药物研发巾特种试剂的现状.特种试剂作为化学药物创新的源头之一,在整个新药研发过程中扮演着不可或缺的角色.近几年各大跨国制药公司加大对药物创新的投入,不断投入巨资用于开发市场上稀有的甚至没有的新颖特种试剂,以占领新药研发和药物创新的制高点.展望了特种试剂未来的发展趋势,以现代药物化学技术和计算化学为核心,根据已知的新药研究趋势以及新药设计理念为依据进行系统性的研究和开发将是主要的方向.     

Natural products as leads for anticancer drug discovery: discovery of new chemotypes of microtubule stabilizers through reengineering of the epothilone scaffold

Epothilones are bacterial macrolides with potent microtubule-stabilizing and antiproliferative activity, which have served as successful lead structures for the discovery of several clinical candidates for cancer treatment. Overall, seven epothilone-type agents have been advanced to clinical evaluation in humans so far and one of these has been approved by the FDA in 2007 for clinical use in breast cancer patients. Notwithstanding these impressive numbers, however, the structural diversity represented by the collection of epothilone analogs that have been (or still are) investigated clinically is rather limited and their individual structures show little divergence from the original natural product leads. In contrast, we have elaborated a series of epothilone-derived macro-lactones, whose overall structural features significantly deviate from those of the natural epothilone scaffold and thus define new structural families of microtubule-stabilizing agents. Key elements of our hypermodification strategy are the change of the natural epoxide geometry from cis to trans, the incorporation of conformationally constrained side chains, the removal of the C(3)-hydroxyl group, and the replacement of C(12) with nitrogen. The latter modification leads to aza-macrolides that may be described as 'non-natural natural products'.     

Wavelet: a new trend in chemistry

Since 1989, wavelet transform (WT) has attracted much interest of chemists working on signal and image processing, and the WT-based techniques have been successfully applied to the chemical signal processing. This approach has been demonstrated as fast in computation with localization and having quick decay properties, in contrast to the popular methods existing, especially to the fast Fourier transform. More than 370 papers have been published up to the year 2002 which covered applications of WT in various fields of chemistry, including analytical chemistry, chemical physics, and quantum chemistry. In this paper, we report on applications of WT to data compression, data smoothing and denoising, baseline and background correction, resolution of multicomponent overlapping signals, regression and classification, and analytical images processing in analytical chemistry. Through this report we wish to induce greater interest of chemists in WT and to obtain greater benefits from using the WT-based techniques.     

Managing laboratory automation: integration and informatics in drug discovery

Drug discovery today requires the focused use of laboratory automation and other resources in combinatorial chemistry and high-throughput screening (HTS). The ultimate value of both combinatorial chemistry and HTS technologies and the lasting impact they will have on the drug discovery process is a chapter that remains to be written. Central to their success and impact is how well they are integrated with each other and with the rest of the drug discovery processes-informatics is key to this success. This presentation focuses on informatics and the integration of the disciplines of combinatorial chemistry and HTS in modern drug discovery. Examples from experiences at Neurogen from the last five years are described.     

Combinatorial chemistry in the discovery and development of drugs

A Comprehensive review of the tractic and strategies that are available to the drug discovery process using combinatorial techniques.     

Revealing atropisomer axial chirality in drug discovery

An often overlooked source of chirality is atropisomerism, which results from slow rotation along a bond axis due to steric hindrance and/or electronic factors. If undetected or not managed properly, this time‐dependent chirality has the potential to lead to serious consequences, because atropisomers can be present as distinct enantiomers or diastereoisomers with their attendant different properties. Herein we introduce a strategy to reveal and classify compounds that have atropisomeric chirality. Energy barriers to axial rotation were calculated using quantum mechanics, from which predicted high barriers could be experimentally validated. A calculated rotational energy barrier of 20 kcal mol^?1 was established as a suitable threshold to distinguish between atropisomers and non‐atropisomers with a prediction accuracy of 86 %. This methodology was applied to subsets of drug databases in the course of which atropisomeric drugs were identified. In addition, some drugs were exposed that were not yet known to have this chiral attribute. The most valuable utility of this tool will be to predict atropisomerism along the drug discovery pathway. When used in concert with our compound classification scheme, decisions can be made during early discovery stages such as “hit‐to‐lead” and “lead optimization,” to foresee and validate the presence of atropisomers and to exercise options of removing, further stabilizing, or rendering the chiral axis of interest more freely rotatable via SAR design, thereby decreasing this potential liability within a compound series. The strategy can also improve drug development plans, such as determining whether a drug or series should be developed as a racemic mixture or as an isolated single compound. Moreover, the work described herein can be extended to other chemical fields that require the assessment of potential chiral axes.     

Evaluating drug efficacy and toxicology in three dimensions: using synthetic extracellular matrices in drug discovery

The acceptance of the new paradigm of 3-D cell culture is currently constrained by the lack of a biocompatible material in the marketplace that offers ease of use, experimental flexibility, and a seamless transition from in vitro to in vivo applications. I describe the development of a covalently cross-linked mimic of the extracellular matrix (sECM), now commercially available, for 3-D culture of cells in vitro and for translational use in vivo. These bio-inspired, biomimetic materials can be used "as is" in drug discovery, toxicology, cell banking, and, ultimately, medicine. For cell therapy and the development of clinical combination products, the sECM biomaterials must be highly reproducible, manufacturable, approvable, and affordable. To obtain integrated, functional, multicellular systems that recapitulate tissues and organs, the needs of the true end users, physicians and patients, must dictate the key design criteria. In chemical terms, the sECM consists of chemically-modified hyaluronan (HA), other glycosaminoglycans (GAGs), and ECM polypeptides containing thiol residues that are cross-linked using biocompatible polyvalent electrophiles. For example, co-cross-linking the semisynthetic thiol-modified HA-like GAG with thiol-modified gelatin produces Extracel as a hydrogel. This hydrogel may be formed in situ in the presence of cells or tissues to provide an injectable cell-delivery vehicle. Alternately, an Extracel hyrogel can be lyophilized to create a macroporous scaffold, which can then be employed for 3-D cell culture. In this Account, we describe four applications of sECMs that are relevant to the evaluation of drug efficacy and drug toxicity. First, the uses of sECMs to promote both in vitro and in vivo growth of healthy cellularized 3-D tissues are summarized. Primary or cell-line-derived cells, including fibroblasts, chondrocytes, hepatocytes, adult and embryonic stem cells, and endothelial and epithelial cells have been used. Second, primary hepatocytes retain their biochemical phenotypes and achieve greater longevity in 3-D culture in Extracel. This constitutes a new 3-D method for rapid evaluation of hepatotoxicity in vitro. Third, cancer cell lines are readily grown in 3-D culture in Extracel, offering a method for rapid evaluation of new anticancer agents in a more physiological ex vivo tumor model. This system has been used to evaluate signal transduction modifiers obtained from our research on lipid signaling. Fourth, a new "tumor engineering" xenograft model uses orthotopic injection of Extracel-containing tumor cells in nude mice. This approach allows production of patient-specific mice using primary human tumor samples and offers a superior metastatic cancer model. Future applications of the injectable cell delivery and 3-D cell culture methods include chemoattractant and angiogenesis assays, high-content automated screening of chemical libraries, pharmacogenomic and toxicogenomic studies with cultured organoids, and personalized treatment models. In summary, the sECM technology offers a versatile "translational bridge" from in vitro to in vivo to facilitate drug discovery in both academic and pharmaceutical laboratories.     

Functionalized carbon nanotubes in drug design and discovery

Carbon nanotubes (CNTs) have been proposed and actively explored as multipurpose innovative carriers for drug delivery and diagnostic applications. Their versatile physicochemical features enable the covalent and noncovalent introduction of several pharmaceutically relevant entities and allow for rational design of novel candidate nanoscale constructs for drug development. CNTs can be functionalized with different functional groups to carry simultaneously several moieties for targeting, imaging, and therapy. Among the most interesting examples of such multimodal CNT constructs described in this Account is one carrying a fluorescein probe together with the antifungal drug amphotericin B or fluorescein and the antitumor agent methotrexate. The biological action of the drug in these cases is retained or, as in the case of amphotericin B constructs, enhanced, while CNTs are able to reduce the unwanted toxicity of the drug administered alone. Ammonium-functionalized CNTs can also be considered very promising vectors for gene-encoding nucleic acids. Indeed, we have formed stable complexes between cationic CNTs and plasmid DNA and demonstrated the enhancement of the gene therapeutic capacity in comparison to DNA alone. On the other hand, CNTs conjugated with antigenic peptides can be developed as a new and effective system for synthetic vaccine applications. What makes CNTs quite unique is their ability, first shown by our groups in 2004, to passively cross membranes of many different types of cells following a translocation mechanism that has been termed the nanoneedle mechanism. In that way, CNTs open innumerable possibilities for future drug discovery based on intracellular targets that have been hard to reach until today. Moreover, adequately functionalized CNTs as those shown in this Account can be rapidly eliminated from the body following systemic administration offering further encouragment for their development. CNT excretion rates and accumulation in organs and any reactivity with the immune system will determine the CNT safety profile and, consequently, any further pharmaceutical development. Caution is advised about the need for systematic data on the long-term fate of these very interesting and versatile nano-objects in correlation with the type of CNT material used. CNTs are gradually plyaing a bigger and more important role in the emerging field of nanomedicine; however, we need to guarantee that the great opportunities they offer will be translated into feasible and safe constructs to be included in drug discovery and development pipelines.     

Interconnected bis-silylenes: a new dimension in organosilicon chemistry

The past two decades have brought remarkable advances in organosilicon chemistry with the isolation of stable silylenes, persila-allene, and disilynes. The extension of this list gives an impression that it will continue to flourish. The judicous employment of sterically appropriate ligands has enabled the synthesis and isolation of compounds with low-valent silicon. Recently, for example, interconnected bis-silylenes were isolated where the two Si atoms are connected by a σ-bond and each Si atom is possessing a lone pair of electrons. The formal oxidation state of each Si atom in the interconnected bis-silylene is +1, so bis-silylenes can be considered as the valence isomers of disilynes. In this Account, we describe the synthesis of interconnected bis-silylenes and assess their potential as a new building block in organosilicon chemistry. In 2009, we reported the isolation of a bis-silylene ((PhC(NtBu)(2))(2)Si(2)) stabilized by a sterically bulky benz-amidinato ligand with tBu substituents on the nitrogen atoms. Prior to our work, Robinson and co-workers described the synthesis of a N-heterocyclic carbene stabilized bis-silylene. In following years, just two more interconnected bis-silylenes have been reported. Density functional theory calculations to establish the geometric and electronic structures of the reported bis-silylenes have shown that the Wiberg bond index (WBI) for all the reported bis-silylenes is ~1. The synthesis of stable (PhC(NtBu)(2))(2)Si(2) prompted explorations of its reactivity. An important facet of silylene chemistry involves oxidative addition at the Si(II) center with unsaturated substrates, a reaction also available for bis-silylenes. Due to the three reaction sites (two lone pairs of electrons and a labile Si(I)-Si(I) single bond) in the interconnected bis-silylenes, we expect novel product formation. A labile Si-Si bond facilitates the reactions of (PhC(NtBu)(2))(2)Si(2) with diphenyl alkyne or adamantyl phosphaalkyne which afforded 1,4- disilabenzene and 1,3-disilacarbaphosphide (CSi(2)P) derivatives, respectively. The former is a noteworthy addition to the silicon analogues of benzene, and the latter serves as a heavy cyclobutadiene. With white phosphorus, a cyclic Si(2)P(2) derivative, an analogue of cyclobutadiene was obtained. The most predominant structural feature of these heavy cyclobutadienes is the presence of two-coordinate P atoms.     

Vapour synthesis: A new technique in synthetic chemistry

Vapour synthesis is the use, as reagents, of vapours which are formed at high temperatures. Typically, vapours, such as those of transition metal atoms, are brought into contact on a cold surface with a substrate, for example an unsaturated hydrocarbon. The ensuing reaction can form compounds, typically organo-transition metal complexes. The principles and methodology are discussed critically to show the applicability of this technique to synthesis and research. A review of recent research illustrating the scope of vapour synthesis is given.