Natural products and Pharma 2011: strategic changes spur new opportunities

Although natural products have been marginalized by major pharmaceutical companies over the last 20-30 years, the changing landscape of drug discovery now favors a greatly enhanced role for Nature's privileged structures. Screening for drug leads in phenotypic screens provides the best opportunity to realize the value of natural products. Advances in total synthesis, especially function-oriented syntheses and biosynthetic technologies offer new avenues for the medicinal chemical optimization of biologically active secondary metabolites. Genomic research has given new insights into biosynthetic processes as well as providing evidence that a wealth of unrealized biosynthetic potential remains to be explored. As Pharma strives to develop innovative and highly effective new drugs, natural products will be increasingly valued as sources of novel leads whose further development will be expedited by emerging technologies.     

芳香类化合物异戊烯基化的研究进展

结构多样的芳香类化合物一直被用作新药发现的线索或主要来源。通过对类药物天然产物进行异戊烯基化结构修饰,能有效提高芳香类化合物生物活性及生物利用度,为新药研究与开发提供简便高效的方法。本文综述了近年来芳香类化合物异戊烯基化的各种方法,以为今后研究提供参考。     

Development of a microfluidic device for the maintenance and interrogation of viable tissue biopsies

A microfluidic based experimental methodology has been developed that offers a biomimetic microenvironment in which pseudo in vivo tissue studies can be carried out under in vitro conditions. Using this innovative technique, which utilizes the inherent advantages of microfluidic technology, liver tissue has been kept in a viable and functional state for over 70 h during which time on-chip cell lysis has been repeatedly performed. Tissue samples were also disaggregated in situ on-chip into individual primary cells, using a collagenase digestion procedure, enabling further cell analysis to be carried out off-line. It is anticipated that this methodology will have a wide impact on biological and clinical research in fields such as cancer prognosis and treatment, drug development and toxicity, as well as enabling better fundamental research into tissue/cell processes.     

Modulation of protein-protein interactions with small organic molecules

Many proteins exert their biological roles as components of complexes, and the functions of proteins are often determined by their specific interactions with other proteins. Because of the central importance of protein-protein interactions for cellular processes, the ability to interfere with specific protein-protein interactions provides a powerful means of influencing the function of selected proteins within the cell. Cell-permeable small organic modulators of protein-protein interactions are thus highly desirable tools both for the study of physiological cellular processes and for the treatment of numerous diseased states. Herein a number of protein-protein interactions that are considered to be pharmaceutical targets are presented, which will familiarize the reader with the strategies that have been employed for the successful identification of small molecule modulators of these protein-protein interactions. These encouraging examples suggest that combined research efforts in the areas of functional proteomics, assay development, and organic synthesis will open up novel possibilities for the treatment of human diseases in the future.     

Targeted therapy vs. DNA-adduct formation-guided design: thoughts about the future of metal-based anticancer drugs

The development of metal-based anticancer drugs is mainly governed by the experience accumulated with cisplatin and its analogues. The synthesis is focused on adding appropriate leaving and non-leaving groups to a transition metal in order to get more favorable DNA binding properties, and the biological activity is tested in vitro, always in a second step, looking for the cell line that is killed at the lowest drug concentration. This strategy seems unproductive today for the area of new drug development where the knowledge on cancer genomics is suggesting the use of targets selectively expressed, or overexpressed by cancer cells. These targets almost always are proteins, constituting membrane receptors or components of crucial biochemical pathways. Some data indicate that the antitumor activity of cisplatin might also be due to the interaction with protein targets. This critical review examines the possibilities for metal-based drugs to challenge tumors with innovative strategies, based on genomic approaches, capitalizing on the chemical experiences with metals in medicine and focusing on the nature of the ligands which are added to a metal depending on the selected tumor cells and on their molecular targets.     

Pattern recognition methods for protein functional site prediction

Protein functional site prediction is closely related to drug design, hence to public health. In order to save the cost and the time spent on identifying the functional sites in sequenced proteins in biology laboratory, computer programs have been widely used for decades. Many of them are implemented using the state-of-the-art pattern recognition algorithms, including decision trees, neural networks and support vector machines. Although the success of this effort has been obvious, advanced and new algorithms are still under development for addressing some difficult issues. This review will go through the major stages in developing pattern recognition algorithms for protein functional site prediction and outline the future research directions in this important area.     

Natural Product-Based Hybrids as Potential Candidates for the Treatment of Cancer: Focus on Curcumin and Resveratrol

One of the main current strategies for cancer treatment is represented by combination chemotherapy. More recently, this strategy shifted to the “hybrid strategy”, namely the designing of a new molecular entity containing two or more biologically active molecules and having superior features compared with the individual components. Moreover, the term “hybrid” has further extended to innovative drug delivery systems based on biocompatible nanomaterials and able to deliver one or more drugs to specific tissues or cells. At the same time, there is an increased interest in plant-derived polyphenols used as antitumoral drugs. The present review reports the most recent and intriguing research advances in the development of hybrids based on the polyphenols curcumin and resveratrol, which are known to act as multifunctional agents. We focused on two issues that are particularly interesting for the innovative chemical strategy involved in their development. On one hand, the pharmacophoric groups of these compounds have been used for the synthesis of new hybrid molecules. On the other hand, these polyphenols have been introduced into hybrid nanomaterials based on gold nanoparticles, which have many potential applications for both drug delivery and theranostics in chemotherapy.     

Bioluminescence and chemiluminescence in drug screening

Drug screening, that is, the evaluation of the biological activity of candidate drug molecules, is a key step in the drug discovery and development process. In recent years, high-throughput screening assays have become indispensable for early stage drug discovery because of the developments in synthesis technologies, such as combinatorial chemistry and automated synthesis, and the discovery of an increasing number of new pharmacological targets.Bioluminescence and chemiluminescence represent suitable detection techniques for high-throughput screening because they allow rapid and sensitive detection of the analytes and can be applied to small-volume samples. In this paper we report on recent applications of bioluminescence and chemiluminescence in drug screening, both for in vitro and in vivo assays. Particular attention is devoted to the latest and most innovative bioluminescence and chemiluminescence-based technologies for drug screening, such as assays based on genetically modified cells, bioluminescence resonance energy transfer (BRET)-based assays, and in vivo imaging assays using transgenic animals or bioluminescent markers. The possible relevance of bioluminescence and chemiluminescence techniques in the future developments of high-throughput screening technologies is also discussed.     

Organic photovoltaic materials and thin-film solar cells

Organic photovoltaic materials are of interest for their future applications in solar cells. Compared to inorganic or dye-sensitized solar cells, organic photovoltaic (OPV) cells offer a huge potential for low-cost large-area solar cells because of their low material consumption per area and easy processing. In the last few years, there have seen an unprecedented growth of interest in OPVs with power conversion efficiency of over 5% attainable. However, OPV’s performance is limited by the narrow light absorption, poor charge carries mobility, and low stability of organic materials, all of which confine its large-scale commercial applications. This review will develop a discussion on the OPV device configuration and operational mechanism after an introduction of the general features of OPV materials. Subsequently, the typical progresses in materials development and performance evolution in recent years will be summarized. The future challenges and prospects faced by organic photovoltaics will be discussed. Finally, the innovative strategy on research of molecular design and device optimization will be suggested with the aim for practical application.     

Design study and heat transfer analysis of a neutron converter target for medical radioisotope production

A worldwide challenge in the near future will be to find a way of producing radioisotopes in sufficient quantity without relying on research reactors. The motivation for this innovative work on targets lies in the accelerator-based production of radioisotopes using a neutron converter target as in the transmutation by adiabatic resonance crossing concept. Thermal analysis of a multi-channel helium cooled device is performed with the computational fluid dynamics code CFX. Different boundary conditions are taken into account in the simulation process and many important parameters such as maximum allowable solid target temperature as well as uniform inlet velocity and outlet pressure changes in the channels are investigated. The results confirm that the cooling configuration works well; hence such a solid target could be operated safely and may be considered for a prototype target.     

Materials for Optical Data Storage

The outstanding feature of materials research in the eighties has been the convergence of basic research and practical application, leading to ever shorter cycles of innovation. This is especially true of materials which form the basis of key technologies. The mass storage units of the next generations of computers will be based on optical processes having a storage density which exceeds that of all hitherto known storage techniques that are practicable from the technical standpoint. In view of the fact that since 1982 read-only memories in the form of compact discs (CD-ROM) have become very successful in the field of audio electronics, research and development are now concentrated on materials for write-once (WORM) and erasable (EDRAW) storage systems. Suitable materials for optical data storage are substances in which data markings can be recorded and deleted respectively using semiconductor lasers. Materials development is centered on the synthesis of infrared-absorbing dyes for WORM memories and the production of rare earth/transition metal alloys for magneto-optical data recording. An introduction to CD-ROM technology will be followed by an overview of the state of development of the most important storage materials which are currently available commercially, and then the properties of these materials will be discussed with reference to selected examples.     

超长碳纳米管的结构调控与制备：进展与挑战

碳纳米管由于其优异的性能和广泛的应用,在过去近三十年中引起了研究者广泛的研究兴趣。在众多不同类型的碳纳米管中,超长碳纳米管由于具有厘米级甚至分米级以上的宏观长度和相对完美的结构,展示出了优异的力学、电学、热学等多方面的优异性能,在透明显示、微电子产业、超强纤维、航空航天等领域具有广阔的应用前景。超长碳纳米管的结构控制制备是充分开发其优异性能并实现其实际应用的关键。在过去二十多年间,超长碳纳米管的研究取得了重要的进展。但同时,在结构控制与批量制备方面也面临巨大的挑战,还存在许多尚未解决的科学与技术难题,从而限制了其实际应用。本文对超长碳纳米管的生长机理、结构控制、选择性制备以及优异性能方面的进展及其背后的创新思想进行了系统的回顾;与此同时,讨论了超长碳纳米管近年来的研究进展、目前面临的挑战和未来的重点攻关方向。期望本文能为超长碳纳米管的可控合成、批量制备以及未来应用提供更多的启发和借鉴,为早日实现高质量超长碳纳米管的宏量制备和产业化起到一些推动作用。     

Rational Approaches for Drug Designing Against Leishmaniasis

Leishmaniasis has been ignored for many years mainly because it plagues remote and poor areas. However, recently, it has drawn attention of several investigators, and active research is going on for antileishmanial drug discovery. The current available drugs have high failure rates and significant side effects. Recently, liposomal preparations of amphotericin B are available and have proved to be a better drug, but they are very expensive. Miltefosine is one of the few orally administered drugs that are effective against Leishmania. However, it has exhibited teratogenicity, hence, should not be administered to pregnant women. Thus, the search for novel and improved antileishmanial drugs continue. A rational approach to design and develop new antileishmanials can be to identify several metabolic and biochemical differences between host and parasite that can be exploited as drug target. Moreover, many natural products also have significant antileishmanial activity and are yet to be exploited. In the current review, we aim to bring together various drug targets of Leishmania, recent development in the field, future prospects, and hope in the area.     

Synthesis and Biomedical Applications of Highly Porous Metal–Organic Frameworks

In this review, aspects of the synthesis, framework topologies, and biomedical applications of highly porous metal–organic frameworks are discussed. The term “highly porous metal–organic frameworks” (HPMOFs) is used to denote MOFs with a surface area larger than 4000 m² g⁻¹. Such compounds are suitable for the encapsulation of a variety of large guest molecules, ranging from organic dyes to drugs and proteins, and hence they can address major contemporary challenges in the environmental and biomedical field. Numerous synthetic approaches towards HPMOFs have been developed and discussed herein. Attempts are made to categorise the most successful synthetic strategies; however, these are often not independent from each other, and a combination of different parameters is required to be thoroughly considered for the synthesis of stable HPMOFs. The majority of the HPMOFs in this review are of special interest not only because of their high porosity and fascinating structures, but also due to their capability to encapsulate and deliver drugs, proteins, enzymes, genes, or cells; hence, they are excellent candidates in biomedical applications that involve drug delivery, enzyme immobilisation, gene targeting, etc. The encapsulation strategies are described, and the MOFs are categorised according to the type of biomolecule they are able to encapsulate. The research field of HPMOFs has witnessed tremendous development recently. Their intriguing features and potential applications attract researchers’ interest and promise an auspicious future for this class of highly porous materials.     

Compounds labelled with short-lived beta(+)-emitting radionuclides and some applications in life sciences. The importance of time as a parameter.

Some examples of recent development of the synthesis of compounds labelled with short-lived beta(+)-emitting radionuclides will be discussed with an emphasis on the importance of time in selecting a synthetic strategy. Furthermore the use of such labelled compounds to monitor certain processes in areas within the field of analytical chemistry and in various applications in drug development will be presented.     

Recent Advances in the Development and Synthesis of Carbohydrate-Based Molecules with Promising Antibacterial Activity

With the rise of antimicrobial resistance (AMR), innovation in antibacterial drug research and development is urgently needed and strongly encouraged by the World Health Organization (WHO). Carbohydrates are valuable bioactive scaffolds to be explored in this context, and because of their unique multifunctionality, stereochemical diversity, and natural protein-binding profile, they come across as attractive starting materials for the synthesis of antimicrobial agents with innovative mechanisms of action (MoA). In this concise review, state-of-the-art methodologies for the synthesis of an array of promising and recently developed carbohydrate-based molecules with antibacterial activity are presented and discussed. By describing successful case studies as platforms for the scrutiny of carbohydrate modification and coupling approaches in organic chemistry, this work summarizes the latest research efforts in this area, ultimately encouraging the design and synthesis of new and much-needed glycoantibiotic leads for pharmaceutical development.     

Mining invertebrate natural products for future therapeutic treasure

This review focuses on biologically active entities from invertebrate sources, especially snails. The reader will encounter several categories of compounds from snails including glycosaminoglycans, peptides, proteins (glycoproteins), and enzymes which possess diverse biological activities. Among glycosaminoglycans, acharan sulfate which was isolated from a giant African snail Acahtina fulica is reviewed extensively. Conotoxins which are also called conopeptides are unique peptide mixtures from marine cone snail. Conotoxins are secreted to capture its prey, and currently have the potential to be highly effective drug candidates. One of the conotoxins is now in the market as a pain killer. Proteins as well as glycoproteins in the snail are known to be involved in the host defense process from an attack of diverse pathogens. Carbohydrate-degrading enzymes characterized and purified in snails are introduced to give an insight into the applicability in glycobiology research such as synthesis and structure characterization of glycoconjugates. It seems that simple snails produce very complicated biological compounds which could be an invaluable source in future therapeutics as well as research areas in natural medicine.     

Is there a future for computational chemistry in drug research?

Improvements in computational chemistry methods have had a growing impact on drug research. But will incremental improvements be sufficient to ensure this continues? Almost all existing efforts to discover new drugs depend on the classic one target, one drug paradigm, although the situation is changing slowly. A new paradigm that focuses on a more systems biology approach and takes account of the reality that most drugs exhibit some level of polypharmacology is beginning to emerge. This will bring about dramatic changes that can significantly influence the role that computational methods play in future drug research. But these changes require that current methods be augmented with those from bioinformatics and engineering if the field is to have a significant impact on future drug research.     

分子筛限域单原子金属催化剂的研究进展

分子筛由于具有规则的微孔孔道结构、 较大的表面积、 优异的(水)热稳定性, 被认为是限域合成超小尺寸金属物种的理想载体. 近年来, 分子筛限域单原子金属催化剂由于超高的金属分散度、 接近100%的金属利用率以及独特的电子结构, 被广泛地应用于重要的催化反应和气体吸附分离过程. 本文系统地总结了近年来分子筛限域不同类型单原子金属催化剂的合成策略, 以及其在多相催化和气体分离等领域的研究进展. 最后, 提出了分子筛限域单原子金属催化剂在合成与表征方面存在的挑战和未来的发展方向.     

Aqueous microwave chemistry: a clean and green synthetic tool for rapid drug discovery

The development of "Greener Organic Chemistry" is due to the recognition that environmentally friendly products and processes will be economical in the long term as they circumvent the need for treating 'end-of-the-pipe' pollutants and by-products generated by conventional synthesis. The fundamentals and significant outcomes of microwave-assisted organic synthesis in aqueous medium are summarized in this tutorial review, which have resulted in the development of relatively sustainable and environmentally benign protocols for the synthesis of drugs and fine chemicals.