多组分反应在合成含肽类药物开发中的应用

多组分反应可以快速大量的合成结构复杂的药物分子,因此现代药物开发与多组分反应的发展密切相关。本文总结了近年来国内外有关多组分反应研究的发展概况及其在含肽链类新药物开发中的应用研究进展。     

Wirkstoffe auf Basis biologisch aktiver Naturstoffe

The potential of natural products as sources for new drugs and lead structures is still largely unexplored and due to their unmatched structural diversity, secondary natural products continue to play a highly significant role in drug discovery. This article gives an overview on different strategies, chemical and biological methods as well as limiting problems for the search, screening, isolation and characterization of bioactive natural products from different sources. Ecological aspects and the importance of biodiversity and sustainable sourcing are also discussed.     

Use of multicomponent, domino, and other one-pot syntheses on solid phase: powerful tools for the generation of libraries of diverse and complex compounds

The availability of small organic molecules covering as much chemical space as possible is seen as the only means that guarantees potential modulation of the many biological targets that are ultimately being unveiled by genomics. Therefore diversity oriented organic synthesis is rapidly becoming one of the paradigms in the process of modern drug discovery. This has spurred research in those fields of chemical investigation that lead to the rapid assembly of not only molecular diversity, but also molecular complexity. As a consequence multi-component as well as domino or related reactions are witnessing a new spring. Coupling these one-pot processes with solid-phase synthesis offers new perspectives for the preparation of both primary and thematic libraries. The progresses recently made in this field that perfectly suits the needs of modern drug discovery are the subject of the present review.     

MCC/SNAr methodology. Part 2: Novel three-step solution phase access to libraries of benzodiazepines

New developments in the search for novel pharmacological agents over the last decade have focused on the preparation of chemical libraries as sources for new leads for drug discovery. To aid this search a plethora of personal synthesizers and new automation technologies have emerged to help fuel the lead discovery engines of drug discovery organizations. In fact, multi-step solid-phase syntheses of diverse libraries in excess of 10,000 products are now feasible via split and mix techniques. At the same time, a multitude of more efficient, diversity or target oriented solution phase chemical methodologies have appeared in the chemical literature, which have enabled the relatively facile construction of successful lead generation libraries with low FTE input and little capital expenditure. This communication reveals a further application of N-BOC-α-aminoaldehydes in the Ugi condensation reaction, followed by a secondary S_NAr cyclization, accessing arrays of biologically relevant benzodiazepines in good yield and overall purity.     

Non-peptidic natural products as ubiquitin-proteasome inhibitors

Approval of bortezomib has validated ubiquitin-proteasome pathway as an important target for treatment of haematological malignancies. However, clinical shortcomings of bortezomib, a covalent peptide proteasome inhibitor, has prompted a paradigm shift in anti-proteasome drug discovery towards development of non-peptidic inhibitors and targeting of upstream ubiquitin system which has drawn traction for interdisciplinary forays. It is being widely recognized that natural products provide valuable leads in the discovery of potent, chemically diverse, non-peptidic inhibitors of 20S proteasome and of key enzymes involved in ubiquitination machinery. As a result, total synthesis of natural, non-peptidic inhibitors of ubiquitin-proteasome pathway has emerged as a critical interlink between organic synthesis, medicinal chemistry, biochemical profiling and drug discovery. An up-to-date account of contextual synthetic challenges, strategies and accomplishments as well as mapping of the chemical diversity space around the natural scaffolds has been captured in this review.     

Quality, not quantity: the role of natural products and chemical proteomics in modern drug discovery

Chemical genetics and reverse chemical genetics parallel classical genetics but target genes at the protein level and have proven useful in recent years for screening combinatorial libraries for compounds of biological interest. However, the performance of combinatorial chemistry in filling pharmaceutical pipelines has been lower than anticipated and the tide may be turning back to Nature in the search for new drug candidates. Even though diversity oriented synthesis is now producing molecules that are natural product-like in terms of size and complexity, these molecules have not evolved to interact with biomolecules. Natural products, on the other hand, have evolved to interact with biomolecules, which is why so many can be found in pharmacopoeias. However, the cellular targets and modes of action of these fascinating compounds are seldom known, hindering the drug development process. This review focuses on the emergence of chemical proteomics and reverse chemical proteomics as tools for the discovery of cellular receptors for natural products, thereby generating protein/ligand pairs that will prove useful in identifying new drug targets and new biologically active small molecule scaffolds. Such a system-wide approach to identifying new drugable targets and their small molecule ligands will help unblock the pharmaceutical product pipelines by speeding the process of target and lead identification.     

Construction of a Meroterpenoid-Like Compounds Library Based on Diversity-Enhanced Extracts

The structural diversity of natural products and their derivatives have long contributed to the development of new drugs. However, the difficulty in obtaining compounds bearing skeletally novel structures has recently led to a decline of pharmaceutical research into natural products. This paper reports the construction of a meroterpenoid-like library containing 25 compounds with diverse molecular scaffolds obtained from diversity-enhanced extracts. This method constitutes an approach for increasing the chemical diversity of natural-product-like compounds by combining natural product chemistry and diversity-oriented synthesis. Extensive pharmacological screening of the library revealed promising compounds for anti-osteoporotic and anti-lymphoma/leukemia drugs. This result indicates that the use of diversity-enhanced extracts is an effective methodology for producing chemical libraries for the purpose of drug discovery.     

The C7N aminocyclitol family of natural products

This review covers microbial secondary metabolites classified in the family of C7N aminocyclitols, a relatively new class of natural products that is increasingly gaining recognition due to their significant biomedical and agricultural uses. Their discovery and structure determinations, their biosynthetic origin, biological properties, chemical synthesis, as well as their further development for pharmaceutical uses are described. The literature from 1970 to July 2002 is reviewed, with 269 references cited.     

Biology-oriented synthesis

Which compound classes are best suited as probes and tools for chemical biology research and as inspiration for medicinal chemistry programs? Chemical space is enormously large and cannot be exploited conclusively by means of synthesis efforts. Methods are required that allow one to identify and map the biologically relevant subspaces of vast chemical space, and serve as hypothesis‐generating tools for inspiring synthesis programs. Biology‐oriented synthesis builds on structural conservatism in the evolution of proteins and natural products. It employs a hierarchical classification of bioactive compounds according to structural relationships and type of bioactivity, and selects the scaffolds of bioactive molecule classes as starting points for the synthesis of compound collections with focused diversity. Navigation in chemical space is facilitated by Scaffold Hunter, an intuitively accessible and highly interactive software. Small molecules synthesized according to BIOS are enriched in bioactivity. They facilitate the analysis of complex biological phenomena by means of acute perturbation and may serve as novel starting points to inspire drug discovery programs.     

Chemical and biological integrity in natural products screening

Due to pressure from combinatorial chemistry and the streamlining of the drug discovery process through automated high-throughput screening technologies, pharmaceutically based natural products programs are under increasing scrutiny. However by taking advantages of technologies originally developed for high-throughput screening and combinatorial chemistry and applying them to processes considered as bottlenecks in classical natural products chemistry (purification, structure elucidation, sample availability) it is our opinion that natural products can still contribute to the effective discovery of novel bioactive and pharmaceutically relevant metabolites. We describe here several such strategies that if universally implemented, will demonstrate i) whether chemical diversity is truly being accessed, ii) that novel metabolites can be formatted in a manner appropriate for modern screening paradigms, and iii) that natural products can be rapidly identified not only for novelty and pharmaceutical relevance but to assess their true biological origin.     

Biotechnological Innovations from Ocean: Transpiring Role of Marine Drugs in Management of Chronic Disorders

Marine drugs are abundant in number, comprise of a diverse range of structures with corresponding mechanisms of action, and hold promise for the discovery of new and better treatment approaches for the management of several chronic diseases. There are huge reserves of natural marine biological compounds, as 70 percent of the Earth is covered with oceans, indicating a diversity of chemical entities on the planet. The marine ecosystems are a rich source of bioactive products and have been explored for lead drug molecules that have proven to be novel therapeutic targets. Over the last 70 years, many structurally diverse drug products and their secondary metabolites have been isolated from marine sources. The drugs obtained from marine sources have displayed an exceptional potential in the management of a wide array of diseases, ranging from acute to chronic conditions. A beneficial role of marine drugs in human health has been recently proposed. The current review highlights various marine drugs and their compounds and role in the management of chronic diseases such as cancer, diabetes, neurodegenerative diseases, and cardiovascular disorders, which has led to the development of new drug treatment approaches.     

PAP inhibitor with in vivo efficacy identified by Candida albicans genetic profiling of natural products

Natural products provide an unparalleled source of chemical scaffolds with diverse biological activities and have profoundly impacted antimicrobial drug discovery. To further explore the full potential of their chemical diversity, we survey natural products for antifungal, target-specific inhibitors by using a chemical-genetic approach adapted to the human fungal pathogen Candida albicans and demonstrate that natural-product fermentation extracts can be mechanistically annotated according to heterozygote strain responses. Applying this approach, we report the discovery and characterization of a natural product, parnafungin, which we demonstrate, by both biochemical and genetic means, to inhibit poly(A) polymerase. Parnafungin displays potent and broad spectrum activity against diverse, clinically relevant fungal pathogens and reduces fungal burden in a murine model of disseminated candidiasis. Thus, mechanism-of-action determination of crude fermentation extracts by chemical-genetic profiling brings a powerful strategy to natural-product-based drug discovery.     

High-throughput screening for bioactive components from traditional Chinese medicine

Throughout the centuries, traditional Chinese medicine has been a rich resource in the development of new drugs. Modern drug discovery, which relies increasingly on automated high throughput screening and quick hit-to-lead development, however, is confronted with the challenges of the chemical complexity associated with natural products. New technologies for biological screening as well as library building are in great demand in order to meet the requirements. Here we review the developments in these techniques under the perspective of their applicability in natural product drug discovery. Methods in library building, component characterizing, biological evaluation, and other screening methods including NMR and X-ray diffraction are discussed.     

Small Molecules of Marine Origin as Potential Anti-Glioma Agents

Marine organisms are able to produce a plethora of small molecules with novel chemical structures and potent biological properties, being a fertile source for discovery of pharmacologically active compounds, already with several marine-derived agents approved as drugs. Glioma is classified by the WHO as the most common and aggressive form of tumor on CNS. Currently, Temozolomide is the only chemotherapeutic option approved by the FDA even though having some limitations. This review presents, for the first time, a comprehensive overview of marine compounds described as anti-glioma agents in the last decade. Nearly fifty compounds were compiled in this document and organized accordingly to their marine sources. Highlights on the mechanism of action and ADME properties were included. Some of these marine compounds could be promising leads for the discovery of new therapeutic alternatives for glioma treatment.     

Diversity‐Oriented Approach for Chemical Biology

Synthetic molecules that modulate and probe biological events are critical tools in chemical biology. Utilizing combinatorial and diversity‐oriented synthetic strategies, access to large numbers of small molecules is becoming more and more feasible, and research groups in this field can take advantage of the power of chemical diversity. Since the majority of early studies were focused on the discovery of compounds that perturb protein functions, diversity‐based approaches are often considered as therapeutic lead discovery tactics. However, the diversity‐oriented approach can also be applied to advance distinct aims, such as target protein identification, or the development of imaging probes and sensors. This review provides a personal perspective of the chemical‐diversity‐based approach and how this principle can be adapted to various chemical biology studies.     

A Small Molecule Inhibits Protein Disulfide Isomerase and Triggers the Chemosensitization of Cancer Cells

Resistance to chemotherapeutic agents represents a major challenge in cancer research. One approach to this problem is combination therapy, the application of a toxic chemotherapeutic drug together with a sensitizing compound that addresses the vulnerability of cancer cells to induce apoptosis. Here we report the discovery of a new compound class ( T8 ) that sensitizes various cancer cells towards etoposide treatment at subtoxic concentrations. Proteomic analysis revealed protein disulfide isomerase (PDI) as the target of the T8 class. In‐depth chemical and biological studies such as the synthesis of optimized compounds, molecular docking analyses, cellular imaging, and apoptosis assays confirmed the unique mode of action through reversible PDI inhibition.     

The impact of plant-pathogen studies on medicinal drug discovery

The pharmaceutical industry is reliant on a constant supply of new chemical entities and molecular targets for disease intervention. In this tutorial review, we want to illustrate that basic research studies on the biological function of natural products involved in plant-pathogen interactions can serve as an inspiring source for the identification of new bioactive entities as well as of strategies on how to achieve small molecule manipulation of biological systems. An application of findings from plant-pathogen interaction studies might therefore display a significant impact on drug discovery.     

Crowdsourcing Natural Products Discovery to Access Uncharted Dimensions of Fungal Metabolite Diversity

A fundamental component for success in drug discovery is the ability to assemble and screen compounds that encompass a broad swath of biologically relevant chemical‐diversity space. Achieving this goal in a natural‐products‐based setting requires access to a wide range of biologically diverse specimens. For this reason, we introduced a crowdsourcing program in which citizen scientists furnish soil samples from which new microbial isolates are procured. Illustrating the strength of this approach, we obtained a unique fungal metabolite, maximiscin, from a crowdsourced Alaskan soil sample. Maximiscin, which exhibits a putative combination of polyketide synthase (PKS), non‐ribosomal peptide synthetase (NRPS), and shikimate pathway components, was identified as an inhibitor of UACC‐62 melanoma cells (LC50=0.93 μM ). The metabolite also exhibited efficacy in a xenograft mouse model. These results underscore the value of building cooperative relationships between research teams and citizen scientists to enrich drug discovery efforts.     

On the remarkable antitumor properties of fludelone: how we got there

Small-molecule natural products are presumably often biosynthesized with a view to optimizing their ability to bind to strategic proteins or other biomolecular targets. Although the ultimate setting in which a drug must function may be very different, the use of such natural products as lead compounds can serve as a significant head start in the hunt for new agents of clinical value. Herein we reveal the synergistic relationship between chemical synthesis and drug optimization in the context of our research program around the epothilones: how synthesis led to the discovery of more-potent epothilone derivatives, and discovery inspired the development of new synthetic routes, thus demonstrating the value of target-directed total synthesis in the quest for new substances of material clinical benefit.     

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.